Peptide REF1 is a local wound signal promoting plant regeneration.

Plants frequently encounter wounding and have evolved an extraordinary regenerative capacity to heal the wounds. However, the wound signal that triggers regenerative responses has not been identified. Here, through characterization of a tomato mutant defective in both wound-induced defense and regeneration, we demonstrate that in tomato, a plant elicitor peptide (Pep), REGENERATION FACTOR1 (REF1), acts as a systemin-independent local wound signal that primarily regulates local defense responses and regenerative responses in response to wounding. We further identified PEPR1/2 ORTHOLOG RECEPTOR-LIKE KINASE1 (PORK1) as the receptor perceiving REF1 signal for plant regeneration. REF1-PORK1-mediated signaling promotes regeneration via activating WOUND-INDUCED DEDIFFERENTIATION 1 (WIND1), a master regulator of wound-induced cellular reprogramming in plants. Thus, REF1-PORK1 signaling represents a conserved phytocytokine pathway to initiate, amplify, and stabilize a signaling cascade that orchestrates wound-triggered organ regeneration. Application of REF1 provides a simple method to boost the regeneration and transformation efficiency of recalcitrant crops.

Five million years of Antarctic Circumpolar Current strength variability.

The Antarctic Circumpolar Current (ACC) represents the world's largest ocean-current system and affects global ocean circulation, climate and Antarctic ice-sheet stability1-3. Today, ACC dynamics are controlled by atmospheric forcing, oceanic density gradients and eddy activity4. Whereas palaeoceanographic reconstructions exhibit regional heterogeneity in ACC position and strength over Pleistocene glacial-interglacial cycles5-8, the long-term evolution of the ACC is poorly known. Here we document changes in ACC strength from sediment cores in the Pacific Southern Ocean. We find no linear long-term trend in ACC flow since 5.3 million years ago (Ma), in contrast to global cooling9 and increasing global ice volume10. Instead, we observe a reversal on a million-year timescale, from increasing ACC strength during Pliocene global cooling to a subsequent decrease with further Early Pleistocene cooling. This shift in the ACC regime coincided with a Southern Ocean reconfiguration that altered the sensitivity of the ACC to atmospheric and oceanic forcings11-13. We find ACC strength changes to be closely linked to 400,000-year eccentricity cycles, probably originating from modulation of precessional changes in the South Pacific jet stream linked to tropical Pacific temperature variability14. A persistent link between weaker ACC flow, equatorward-shifted opal deposition and reduced atmospheric CO2 during glacial periods first emerged during the Mid-Pleistocene Transition (MPT). The strongest ACC flow occurred during warmer-than-present intervals of the Plio-Pleistocene, providing evidence of potentially increasing ACC flow with future climate warming.

Membralin is required for maize development and defines a branch of the endoplasmic reticulum-associated degradation pathway in plants.

Endoplasmic reticulum (ER)-associated degradation (ERAD) plays key roles in controlling protein levels and quality in eukaryotes. The Ring Finger Protein 185 (RNF185)/membralin ubiquitin ligase complex was recently identified as a branch in mammals and is essential for neuronal function, but its function in plant development is unknown. Here, we report the map-based cloning and characterization of Narrow Leaf and Dwarfism 1 (NLD1), which encodes the ER membrane-localized protein membralin and specifically interacts with maize homologs of RNF185 and related components. The nld1 mutant shows defective leaf and root development due to reduced cell number. The defects of nld1 were largely restored by expressing membralin genes from Arabidopsis thaliana and mice, highlighting the conserved roles of membralin proteins in animals and plants. The excessive accumulation of ß-hydroxy ß-methylglutaryl-CoA reductase in nld1 indicates that the enzyme is a membralin-mediated ERAD target. The activation of bZIP60 mRNA splicing-related unfolded protein response signaling and marker gene expression in nld1, as well as DNA fragment and cell viability assays, indicate that membralin deficiency induces ER stress and cell death in maize, thereby affecting organogenesis. Our findings uncover the conserved, indispensable role of the membralin-mediated branch of the ERAD pathway in plants. In addition, ZmNLD1 contributes to plant architecture in a dose-dependent manner, which can serve as a potential target for genetic engineering to shape ideal plant architecture, thereby enhancing high-density maize yields.

The maize PLASTID TERMINAL OXIDASE (PTOX) locus controls the carotenoid content of kernels.

Carotenoids perform a broad range of important functions in humans; therefore, carotenoid biofortification of maize (Zea mays L.), one of the most highly produced cereal crops worldwide, would have a global impact on human health. PLASTID TERMINAL OXIDASE (PTOX) genes play an important role in carotenoid metabolism; however, the possible function of PTOX in carotenoid biosynthesis in maize has not yet been explored. In this study, we characterized the maize PTOX locus by forward- and reverse-genetic analyses. While most higher plant species possess a single copy of the PTOX gene, maize carries two tandemly duplicated copies. Characterization of mutants revealed that disruption of either copy resulted in a carotenoid-deficient phenotype. We identified mutations in the PTOX genes as being causal of the classic maize mutant, albescent1. Remarkably, overexpression of ZmPTOX1 significantly improved the content of carotenoids, especially ß-carotene (provitamin A), which was increased by ~threefold, in maize kernels. Overall, our study shows that maize PTOX locus plays an important role in carotenoid biosynthesis in maize kernels and suggests that fine-tuning the expression of this gene could improve the nutritional value of cereal grains.

The repertoire of copy number alteration signatures in human cancer.

Copy number alterations (CNAs) are a predominant source of genetic alterations in human cancer and play an important role in cancer progression. However comprehensive understanding of the mutational processes and signatures of CNA is still lacking. Here we developed a mechanism-agnostic method to categorize CNA based on various fragment properties, which reflect the consequences of mutagenic processes and can be extracted from different types of data, including whole genome sequencing (WGS) and single nucleotide polymorphism (SNP) array. The 14 signatures of CNA have been extracted from 2778 pan-cancer analysis of whole genomes WGS samples, and further validated with 10 851 the cancer genome atlas SNP array dataset. Novel patterns of CNA have been revealed through this study. The activities of some CNA signatures consistently predict cancer patients' prognosis. This study provides a repertoire for understanding the signatures of CNA in cancer, with potential implications for cancer prognosis, evolution and etiology.

Crown Ether Electrolyte Additive Enables High-Rate and Stable Polyviologen Cathode Material for Chloride Ion Batteries.

A variety of inorganic and inorganic cathode materials for chloride ion storage are reported. However, their application in chloride ion batteries (CIB) is hindered by poor rate capability and cycling stability. Herein, an organic poly(butyl viologen dichloride) (PBVCl2) cathode material with significantly enhanced rate and cycling performance in the CIB is achieved using a crown ether (18-Crown-6) additive in the tributylmethylammonium chloride-based electrolyte. The as-prepared PBVCl2 cathodes exhibit impressive capacity increases from 149.4 to 179.1 mAh g-1 at 0.1 C and from 57.8 to 111.9 mAh g-1 at 10 C, demonstrating the best rate performance with the highest energy density among those of various reported cathodes for CIBs. This impressive performance improvement is a result of the great boosts in charge transfer, ion transport, and interface stability of the battery by the use of 18-Crown-6, which also contributes to a more than twofold increase in capacity retention after 120 cycles. The electrode reaction mechanism of the CIB based on highly reversible chloride ion transfer is revealed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy.

Prediction model for EBV infection following HLA haploidentical matched hematopoietic stem cell transplantation.

AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies. However, viral infections, particularly EBV infection, frequently occur following allo-HSCT and can result in multi-tissue and organ damage. Due to the lack of effective antiviral drugs, these infections can even progress to post-transplant lymphoproliferative disorders (PTLD), thereby impacting the prognosis. In light of this, our objective is to develop a prediction model for EBV infection following allo-HSCT. METHODS: A total of 466 patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between September 2019 and December 2020 were included in this study. The patients were divided into a development cohort and a validation cohort based on the timing of their transplantation. Our aim was to develop and validate a grading scale using these cohorts to predict the risk of EBV infection within the first year after haplo-HSCT. Additionally, single-cell RNA sequencing (sc-RNAseq) data from the bone marrow of healthy donors were utilized to assess the impact of age on immune cells and viral infection. RESULTS: In the multivariate logistic regression model, four predictors were retained: donor age, female-to-male transplant, graft MNC (mononuclear cell) dose, and CD8 dose. Based on these predictors, an EBV reactivation predicting score system was constructed. The scoring system demonstrated good calibration in both the derivation and validation cohorts, as confirmed by the Hosmer-Lemeshow test (p > 0.05). The scoring system also exhibited favorable discriminative ability, as indicated by the C statistics of 0.72 in the derivation cohort and 0.60 in the validation cohort. Furthermore, the clinical efficacy of the scoring system was evaluated using Kaplan-Meier curves based on risk ratings. The results showed significant differences in EBV reactivation rates between different risk groups, with p-values less than 0.001 in both the derivation and validation cohorts, indicating robust clinical utility. The analysis of sc-RNAseq data from the bone marrow of healthy donors revealed that older age had a profound impact on the quantity and quality of immune subsets. Functional enrichment analysis highlighted that older age was associated with a higher risk of infection. Specifically, CD8 + T cells from older individuals showed enrichment in the pathway of "viral carcinogenesis", while older CD14 + monocytes exhibited enrichment in the pathway of "regulation of viral entry into host cell." These findings suggest that older age may contribute to an increased susceptibility to viral infections, as evidenced by the altered immune profiles observed in the sc-RNAseq data. CONCLUSION: Overall, these results demonstrate the development and validation of an effective scoring system for predicting EBV reactivation after haplo-HSCT, and provide insights into the impact of age on immune subsets and viral infection susceptibility based on sc-RNAseq analysis of healthy donors' bone marrow.

Tunable high energy pulse generation in the range of 2.9-3.6†µm enabled by an actively Q switched Er3+/Dy3+ codoped fluoride fiber oscillator.

We demonstrate, for the first time, an actively Q switched red-diode-clad-pumped Er3+/Dy3+ codoped fluoride fiber oscillator. Its wavelength can be continuously tuned over the range of 2.906-3.604 µm (698 nm), representing the widest tuning span of pulsed fluoride fiber oscillators in the mid-infrared. In addition, the achieved pulse energy at each wavelength of >2.95 µm is also higher than that of a previously reported pulsed fluoride fiber oscillator at the corresponding wavelength, to the best of our knowledge. By tuning the wavelength to 3.204 µm, the highest pulse energy of 82 µJ has been gotten with a pulse width of 520 ns at a repetition rate of 500 Hz.

Deep-learning-assisted sidewall profiling white light interferometry system for accurately measuring 3D profiles and surface roughness on the groove sidewalls of precision components.

The accurate measurement of surface three-dimensional (3D) profile and roughness on the groove sidewalls of components is of great significance to diverse fields such as precision manufacturing, machining processes, energy transportation, medical equipment, and semiconductor industry. However, conventional optical measurement methods struggle to measure surface profiles on the sidewall of a small groove. Here, we present a deep-learning-assisted sidewall profiling white light interferometry system, which consists of a microprism-based interferometer, an optical path compensation device, and a convolutional neural network (CNN), for the accurate measurement of surface 3D profile and roughness on the sidewall of a small groove. We have demonstrated that the sidewall profiling white light interferometry system can achieve a measurement accuracy of 2.64 nm for the 3D profile on a groove sidewall. Moreover, we have demonstrated that the CNN-based single-image super-resolution (SISR) technique could improve the measurement accuracy of surface roughness by over 30%. Our system can be utilized in cases where the width of the groove is only 1 mm and beyond, limited only by the size of the microprism and the working distance of the objective used in our system.

Targeting TFH cells is a novel approach for donor-specific antibody desensitization of allograft candidates: an in vitro and in vivo study.

The presence of donor-specific antibodies (DSA) are associated with graft failure either following human leukocyte antigen (HLA)-mismatched allogeneic stem cell transplantation or after organ transplantation. Although targeting B cells and plasma cells have been used for desensitization, there have been reports of failure. T-follicular helper (Tfh) cells assist B cells in differentiating into antibody-secreting plasma cells. We used haploidentical allograft as a platform to investigate the possibility of targeting Tfh cells to desensitize DSA. The quantities of circulating Tfh (cTfh) cell subsets in allograft candidates were abnormal, and these cells, including the cTfh2 and cTfhem cell subsets, were positively related to the production of anti-HLA antibodies. Ex vivo experiments showed that the cTfh cells of anti-HLA antibody-positive allograft candidates could induce B cells to differentiate into DSA-producing plasmablasts. The immune synapse could be involved in the assistance of cTfh cells to B cells in antibody production. In vitro experiments and in vivo clinical pilot studies indicated that targeting cTfh cells with sirolimus can inhibit their auxiliary function in assisting B cells. Ex vivo and in vivo studies demonstrated the effect of sirolimus and rituximab on DSA desensitization compared with either sirolimus or rituximab alone (60%, 43.75%, and 30%, respectively). Our findings provide new insight into the role of Tfh cells in the pathogenesis of DSA production in HLA-mismatched transplant candidates. Our data also indicate that targeting Tfh cells is a novel strategy for DSA desensitization and combination of sirolimus and rituximab might be a potential therapy. The prospective cohort of this study is registered at http://www.chictr.org.cn as #ChiCTR-OPC-15006672.

CD56bright NK cell expansion correlated with EBV reactivation control post allogeneic hematopoietic stem cell transplantation.

Natural killer (NK) cells are equipped with anti-Epstein-Barr virus (EBV) function, however, whether EBV infection will affect NK cells reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. To identify the characteristics of NK cells, we prospectively enrolled 11 patients who occurred EBV reactivation post allo-HSCT and 11 patients without EBV infection as control. We found that that EBV infection induced the expansion of CD56bright and NKG2A+KIR- NK subsets,and decreased the cytotoxicity function of NK cells. The frequency of NKG2A+KIR- NK cells were higher in patients who progressed into post-transplant lymphoproliferative disorder (PTLD) than EBV viremia patients, which also correlated with decreased proliferation and cytotoxic function. By screening the activation receptors of NK cells, we found the DNAM-1+CD56bright NK cells is significantly increased after EBV stimulation, further we demonstrated that DNAM-1 is essential for EBV induced NK cells activation as the cytokine release against EBV-transformed lymphoblastoid cell lines(EBV-LCLs) of CD56bright NK cells were significantly decreased after DNAM-1 blockade. NK cells infusion suppressed the progression of EBV-related tumor mice model. A prospective cohort indicated that old donor age was an independent risk factor for EBV infection. Rapid CD56bri expansion and high expression of DNAM-1 on CD56bri NK cells in response to EBV reactivation correlated with rapid EBV clearance post allo-HSCT in patients with younger donors. In summary, our data showed that high expression of DNAM-1 receptors on NK cell may participate protective CD56bri NK cells response to EBV infection after allo-HSCT.

A predictive model of herpes zoster after allogeneic hematopoietic stem cell transplantation: VZV reactivation following antiviral prophylaxis discontinuation.

Herpes zoster (HZ) refers to the rash appearing on dermatomes due to varicella zoster virus (VZV) reactivation. The incidence of HZ is significantly higher in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients than in non-HSCT recipients. Although acyclovir prophylaxis is routinely administered to every allo-HSCT recipient for 1 year after transplantation, some individuals eventually develop late-onset HZ after completing prophylaxis. Little information is known about the clinical features of HZ after prophylactic antiviral treatment discontinuation, and an effective predictive model of late-onset HZ needs to be established. A total of 3366 patients who had received allo-HSCT from 2012 to 2017 were included in our study, among whom 201 developed HZ after 1 year (late-onset HZ). We designed a nested case-control study to identify potential predictors of late-onset HZ. Finally, we established a predictive model using binary logistic regression analysis. Age (p < .001), use of immunosuppressants at +1 year (p < .001), CD4-CD8 ratio at +1 year (p < .001), certain mental disorders (depression, anxiety, insomnia and adjustment disorder) (p < .001), engraftment time of neutrophils (p < .001), and CD8+ cell count at +30 days (p < .001) were independent predictors of late-onset HZ. A risk grading system was established based on regression coefficients. Discrimination and calibration analysis indicated that the model had good performance. We also identified several predictive factors of the incidence of HZ-related complications. This is the first scoring system for predicting the incidence of late-onset HZ after allo-HSCT. This model can be applied to identify individuals at high risk of late-onset HZ in the early period after receiving allo-HSCT.

Safety and efficacy of baricitinib in steroid-resistant or relapsed immune thrombocytopenia: An open-label pilot study.

Patients with steroid-resistant or relapsed immune thrombocytopenia (ITP) suffer increased bleeding risk and impaired quality of life. Baricitinib, an oral Janus-associated kinases (JAK) inhibitor, could alleviate both innate and adaptive immune disorders without inducing thrombocytopenia in several autoimmune diseases. Accordingly, an open-label, single-arm, phase 2 trial (NCT05446831) was initiated to explore the safety and efficacy of baricitinib in ITP. Eligible patients were adults with primary ITP who were refractory to corticosteroids and at least one subsequent treatment, and had platelet counts below 30 × 109/L at enrolment. Participants received baricitinib 4 mg daily for 6 months. The primary endpoint was durable response at the 6-month follow-up. A total of 35 patients were enrolled. Durable response was achieved in 20 patients (57.1%, 95% confidence interval, 39.9 to 74.4), and initial response in 23 (65.7%) patients. For patients responding to baricitinib, the median time to response was 12 (IQR 6-20) days, and the median peak platelet count was 94 (IQR 72-128) × 109/L. Among the 27 patients undergoing extend observation, 12 (44.4%) remained responsive for a median duration of approximately 20 weeks after baricitinib discontinuation. Adverse events were reported in 11 (31.4%) patients, including infections in 6 (17.1%) patients during the treatment period. Treatment discontinuation due to an adverse event was reported in 2 (5.7%) patients. Evidence from this pilot study suggested that baricitinib might be a novel candidate for the armamentarium of ITP-modifying agents. Future studies are warranted to validate the safety, efficacy, and optimal dosing of baricitinib in patients with ITP.

Functional Competence of NK Cells via the KIR/MHC Class I Interaction Correlates with DNAM-1 Expression.

The interaction of inhibitory receptors with self-MHC class I (MHC-I) molecules is responsible for NK cell education. The intensity of DNAM-1 expression correlates with NK cell education. However, whether DNAM-1 expression directly influences the functional competence of NK cells via the KIR/MHC-I interaction remains unclear. Based on allogeneic haploidentical hematopoietic stem cell transplantation, we investigated the intensity of DNAM-1 expression on reconstituted NK cells via the interaction of KIR with both donor HLA and recipient HLA at days 30, 90, and 180 after hematopoietic stem cell transplantation. The reconstituted NK cells educated by donor and recipient HLA molecules showed the highest DNAM-1 expression, whereas DNAM-1 expression on educated NK cells with only recipient HLA molecules was higher than that on educated NK cells with only donor HLA molecules, indicating that NK cells with donor or recipient HLA molecules regulate DNAM-1 expression and thereby affect NK cell education. Additionally, the effects of recipient cells on NK cell education were greater than those of donor cells. However, only when the DNAM-1, NKP30, and NKG2D receptors were blocked simultaneously was the function of educated and uneducated NK cells similar. Therefore, activating receptors may collaborate with DNAM-1 to induce educated NK cell hyperresponsiveness. Our data, based on in vitro and in vivo studies, demonstrate that the functional competence of NK cells via the KIR/MHC-I interaction correlates with DNAM-1 expression in human NK cells.

Efficient Fabrication of Bioinspired Flexible Pressure Sensors via Electrohydrodynamic Jet Printing Method.

Bioinspired microdevices have made significant strides in various applications including human motion and health detection. However, facile and highly efficient fabrication approach of flexible pressure sensors remains a great challenge. Herein, inspired by the gecko's foot structure, a flexible pressure sensor with microdomes structure is fabricated by tip-assisted on-demand electrohydrodynamic jet (EHD-jet) printing method. Ascribed to the interlocking electrodes with microdome structure, 3D deformation rates are substantially enlarged. When the microdromes structure is under pressure, the resistivity of carbon nanotubes film coated on the surface of microdomes structure will change remarkably. By using the combined effect of assisted tip and ring focusing electrode, the influence and constraints on microstructure fabrication caused by substrate material and morphology are minimized. The desired uniform structures can be adjusted rapidly by changing the printing parameters and liquid properties. High length-height ratio (0.64) of microdomes enhances sensitivity, with minimum detection limit is 2 Pa and response time is 40 ms. Finally, the bionic flexible sensor indicated excellent performance in capable of detecting pressure, sound vibrations and human motion. This work presents a new method for high-efficiency fabrication micro-nano patterns for flexible sensors inspired, which could be used in wearable tech and health monitoring.

Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease.

Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFß and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.

Associations of three differential white blood cell counts, platelet counts, and their derived inflammatory indices with cancer-related fatigue in patients with breast cancer undergoing chemotherapy.

PURPOSE: Inflammation is thought to be a vital element in the etiology of cancer-related fatigue (CRF), and circulating blood cell parameters could be important markers of inflammatory response. However, the associations of several major blood cell counts and their derived inflammatory indices with CRF are not well described. The present study aimed to establish whether a relationship exists between the counts of three white blood cell (WBC) types, platelets, and CRF and investigate whether several systemic inflammatory indices were associated with CRF in patients with breast cancer (BC). METHODS: A cross-sectional survey was conducted with a sample of 824 patients with BC undergoing chemotherapy. The cancer fatigue scale was administered to assess CRF. Hematological indicators, including neutrophils, lymphocytes, monocytes, and platelets, were retrieved from routine blood test. Network analyses were used to examine the associations among them. RESULTS: Among 824 participants, the mean score of CRF was (27 ± 10), ranging from 0 to 57. The results of network models indicated that physical fatigue was negatively linked to lymphocyte counts (weight = - 0.161), and affective fatigue was positively associated with neutrophil counts (weight = 0.070). Additionally, physical fatigue was positively linked to the platelet-to-lymphocyte ratio (PLR) (weight = 0.049). CONCLUSION: There were preliminary associations of counts of three WBC types, platelet counts, and systemic inflammatory indices, with distinct dimensions of CRF in patients with BC. Findings provide empirical support for the cellular basis of fatigue-associated inflammatory states.

Beyond hype: unveiling the Real challenges in clinical translation of 3D printed bone scaffolds and the fresh prospects of bioprinted organoids.

Bone defects pose significant challenges in healthcare, with over 2 million bone repair surgeries performed globally each year. As a burgeoning force in the field of bone tissue engineering, 3D printing offers novel solutions to traditional bone transplantation procedures. However, current 3D-printed bone scaffolds still face three critical challenges in material selection, printing methods, cellular self-organization and co-culture, significantly impeding their clinical application. In this comprehensive review, we delve into the performance criteria that ideal bone scaffolds should possess, with a particular focus on the three core challenges faced by 3D printing technology during clinical translation. We summarize the latest advancements in non-traditional materials and advanced printing techniques, emphasizing the importance of integrating organ-like technologies with bioprinting. This combined approach enables more precise simulation of natural tissue structure and function. Our aim in writing this review is to propose effective strategies to address these challenges and promote the clinical translation of 3D-printed scaffolds for bone defect treatment.

Inhibition of autophagy via 3-methyladenine alleviates the progression of preeclampsia.

Autophagy is a cellular mechanism for self-renewal that involves the breakdown of cytoplasmic proteins or organelles within lysosomes. Although preeclampsia (PE) exhibits several characteristics that could imply disrupted autophagy, there is limited evidence supporting the notion that impaired placental autophagy directly causes PE, as indicated by differential expression profiling of whole placental tissue. In this study, we aim to explore the significance of autophagy in maintaining pregnancy and its association with PE. First, the RNA-seq results show that 218 genes are differentially expressed in placentas from preeclamptic pregnancies. Notably, KEGG pathway analysis reveals significant enrichment of genes related to autophagy-related signaling pathways, including the PI3K-Akt signaling pathway, the AMPK signaling pathway, and the mTOR signaling pathway. Additionally, our findings indicate an increase in autophagy in placentas from pregnancies complicated by preeclampsia as well as in trophoblasts subjected to hypoxic conditions. Next, we examine the impact of 3-methyladenine (3-MA), a targeted inhibitor of autophagy, on the progression of PE. The administration of 3-MA profoundly alleviates the severity of PE-like symptoms in rats subjected to reduced uterine perfusion pressure (RUPP). The findings from our study suggest that inhibiting autophagy may serve as a promising approach for adjuvant chemotherapy for PE.

Copy number signature analysis tool and its application in prostate cancer reveals distinct mutational processes and clinical outcomes.

Genome alteration signatures reflect recurring patterns caused by distinct endogenous or exogenous mutational events during the evolution of cancer. Signatures of single base substitution (SBS) have been extensively studied in different types of cancer. Copy number alterations are important drivers for the progression of multiple cancer. However, practical tools for studying the signatures of copy number alterations are still lacking. Here, a user-friendly open source bioinformatics tool "sigminer" has been constructed for copy number signature extraction, analysis and visualization. This tool has been applied in prostate cancer (PC), which is particularly driven by complex genome alterations. Five copy number signatures are identified from human PC genome with this tool. The underlying mutational processes for each copy number signature have been illustrated. Sample clustering based on copy number signature exposure reveals considerable heterogeneity of PC, and copy number signatures show improved PC clinical outcome association when compared with SBS signatures. This copy number signature analysis in PC provides distinct insight into the etiology of PC, and potential biomarkers for PC stratification and prognosis.