First Report of Root-Knot Nematode (Meloidogyne incognita) on Dioscorea opposita in Henan Province, China.

Dioscorea opposita is an annual twining plant in China that is used for consumption and medicinal purposes. The planting area of D. opposita is near 500,000 hectares in China, mainly in Shangdong, Hebei, Henan, Jiangxi and Yunnan provinces. In August 2021, we observed that some D. opposita plants grew poorly with smaller and chlorotic leaves in Changyuan (35°8'12"N; 114°43'52"E), Henan Province, China. Galls with hook-shaped roots and tuber damage were also observed, typical of root-knot nematode. Thirty tubers were randomly collected and 60% were infested with root-knot nematodes. During a disease survey in Changyuan, the incidences of root-knot nematode damage were 31.5%, 21%, and 18% in three fields (0.33, 0.67, and 4 ha, respectively) at harvest. The average tuber length of infected plants was decreased by 65.8%, and the average weight was decreased by 70.1% compared to the healthy plants. Males, females, second-stage juveniles (J2s), and eggs were extracted from individual diseased tubers from the three fields for morphological identification. Females were white, pear-shaped with a projecting neck. Males showed a trapezoidal labial region with prominent stylet knobs, including a high head cap which had a stepped outline and was centrally concave in lateral view. Morphological measurements are described in the supplementary material. All data and descriptions conformed to the morphological characteristics of Meloidogyne incognita. Genomic DNA was extracted from J2s (n=9) using PCR lysis buffer, and used for PCR amplification of the sequence characterized amplified region (SCAR) markers specific for M. incognita. Two pairs of the SCAR primers, Mi-F/Mi-R, and Inc-K14-F/Inc-K14-R, were used to diagnose whether these nematodes from D. opposita were M. incognita (Meng et al. 2004; Randig et al. 2002). The PCR produced expected amplification products of 955 and 399 bp, confirming the nematode to be M. incognita. Primers specific for M. arenaria (Far/Rar) and M. javanica (Fjav/Rjav) were used but failed to amplify fragments (Randig et al. 2002; Zijlstra et al. 2000). The obtained PCR fragments were sequenced and deposited in GenBank (accession no. OQ420602.1, OQ427638.1). They showed 99.9 and 100% identity to the available GenBank M. incognita sequence (accession no. MK410954.1, ON861825.1), respectively. A pathogenicity test was conducted in greenhouse conditions. Bulbils of D. opposita were sown in the pots filled with 2,000 ml of autoclaved soil mixture (loamy soil/sand, 1:1). One month later, 15 seedlings (five to six leaf stage) were inoculated with 1,000 M. incognita J2s individually. Five plants without nematode inoculation were used as the control. Two months after inoculation, all of the inoculated roots had galling symptoms similar to those observed in the field, and 100% of root system tissues had galls. The root gall index was ~6 according to a 0 to 10 RKN damage rating scale (Poudyal et al. 2005). No symptoms were found on the control plants. The nematodes were reisolated from root tissue and identified. M. incognita has a broad host range in many species of economic importance including Salvia miltiorrhiza (Wen et al. 2023), Ipomoea batatas (Maleita et al. 2022), and Zea mays (López-Robles et al. 2013). So far, M. incognita has been reported in D. alata and D. rotundata in Africa (Onkendi et al. 2014). To our best knowledge, this is the first record of M. incognita on D. opposita in Henan Province, China. With the increased planting area of D. opposita in China, root-knot nematodes are becoming more serious and reducing tuber production, with yield losses more than 60%. This identification is a preliminary step in developing effective disease management schemes. Declaration of interest The authors declare no conflict of interest. Funding This work was financially supported by the Key Scientific Research Projects of Higher Education Institutions of Henan Province (21A180013), China Agriculture Research System (CARS-21), The Zhongyuan high level talents special support plan-Science and Technology Innovation Leading Talents (224200510011) and Science and Technology Research Project of Henan Province (222102310211). References López-Robles, J., et al. 2013. Plant Dis. 97:694. https://doi.org/10.1094/PDIS-07-12-0674-PDN. Maleita, C., et al. 2022. Plant Dis. 106:2536. https://doi.org/10.1094/PDIS-12-21-2680-PDN. Meng, Q. P., et al. 2004. Acta Phytopathol. Sinica 34:204. https://doi.org/10.13926/j.cnki.apps.2004.03.003. Onkendi, E. M., et al. 2014. Plant Pathol. 63:727. https://doi.org/10.1111/ppa.12202. Poudyal, D. S., et al. 2005. Australas. Plant Pathol. 34:181. https://doi.org/10.1071/AP05011. Randig, O., et al. 2002. Genome 45:862. https://doi.org/10.1139/g02-054. Wen, Y., et al. 2023. Plant Dis. Accepted. https://doi.org/10.1094/PDIS-05-22-0997-PDN. Zijlstra, C., et al. 2000. Nematology 2:847. https://doi.org/10.1163/156854100750112798.

Self-assembled nanocomposites of carboxymethyl ß-dextran/protamine sulfate for enhanced chemotherapeutic drug sensitivity of triple-negative breast cancer by autophagy inhibition via a ternary collaborative strategy.

Drug resistance in cancer chemotherapy is a major confounding factor affecting the effectiveness of chemotherapeutic agents, thereby leading to poor clinical outcomes. Most chemotherapeutic drugs can induce protective autophagy and increase the resistance of tumors to chemotherapeutic drugs and reduce effective drug delivery to tumor cells. In this study, a tri-drug nanocomposite (NP) delivery system was devised using carboxymethyl ß-dextran (CMD) and protamine sulfate (PS), two natural materials with good bio-compatibility. They were designed to carry the chemotherapeutic drug docetaxel (DTX), the autophagy inhibitor chloroquine (CQ), and Atg5 siRNA to cancer cells. The CQ + DTX + Atg5 siRNA NPs was driven by electrostatic interaction and self-assembly methods. The breast cancer cell line MDA-MB-231 was used for both cell culture and establishing mouse xenograft model. Our findings demonstrated that CQ and Atg5 siRNA encapsulated in NPs could enhance the sensitivity of tumor cells to DTX. The NPs exhibited remarkable considerable therapeutic effects for treating triple-negative breast cancer (TNBC) and good biosafety. Therefore, we established a novel multifunctional nanoplatform based on CMD and PS that enhances chemotherapeutic drug sensitivity through an autophagy inhibition strategy, providing new opportunities to overcome conventional drug resistance and enhance therapeutic efficiency against TNBC.

Interaction of AcMADS68 with transcription factors regulates anthocyanin biosynthesis in red-fleshed kiwifruit.

In red-fleshed kiwifruit, anthocyanin pigmentation is a crucial commercial trait. The MYB-bHLH-WD40 (MBW) complex and other transcription factors regulate its accumulation. Herein, a new SEP gene, AcMADS68, was identified as a regulatory candidate for anthocyanin biosynthesis in the kiwifruit by transcriptome data and bioinformatic analyses. AcMADS68 alone could not induce the accumulation of anthocyanin both in Actinidia arguta fruit and tobacco leaves. However, in combination with AcMYBF110, AcMYB123, and AcbHLH1, AcMADS68 co-overexpression increased anthocyanin biosynthesis, whereas its silencing reduced anthocyanin accumulation. The results of the dual-luciferase reporter, firefly luciferase complementation, yeast two-hybrid and co-immunoprecipitation assays showed that AcMADS68 could interact with both AcMYBF110 and AcMYB123 but not with AcbHLH1, thereby co-regulating anthocyanin biosynthesis by promoting the activation of the target genes, including AcANS, AcF3GT1, and AcGST1. Moreover, AcMADS68 also could activate the promoter of AcbHLH1 surported by dual-luciferase reporter and yeast one-hybrid assays, thereby further amplifying the regulation signals from the MBW complex, thus resulting in enhanced anthocyanin accumulation in the kiwifruit. These findings may facilitate better elucidation of various regulatory mechanisms underlying anthocyanin accumulation and contribute to the quality enhancement of red-fleshed kiwifruit.

Allelic variation of MdMYB123 controls malic acid content by regulating MdMa1 and MdMa11 expression in apple.

Acidity is a key determinant of fruit organoleptic quality. Here, a candidate gene for fruit acidity, designated MdMYB123, was identified from a comparative transcriptome study of two Ma1Ma1 apple (Malus domestica) varieties, 'Qinguan (QG)' and 'Honeycrisp (HC)' with different malic acid content. Sequence analysis identified an A→T SNP, which was located in the last exon, resulting in a truncating mutation, designated mdmyb123. This SNP was significantly associated with fruit malic acid content, accounting for 9.5% of the observed phenotypic variation in apple germplasm. Differential MdMYB123- and mdmyb123-mediated regulation of malic acid accumulation was observed in transgenic apple calli, fruits, and plantlets. Two genes, MdMa1 and MdMa11, were up- and down-regulated in transgenic apple plantlets overexpressing MdMYB123 and mdmyb123, respectively. MdMYB123 could directly bind to the promoter of MdMa1 and MdMa11, and induce their expression. In contrast, mdmyb123 could directly bind to the promoters of MdMa1 and MdMa11, but with no transcriptional activation of both genes. In addition, gene expression analysis in 20 different apple genotypes based on SNP locus from 'QG' x 'HC' hybrid population confirmed a correlation between A/T SNP with expression levels of MdMa1 and MdMa11. Our finding provides valuable functional validation of MdMYB123 and its role in the transcriptional regulation of both MdMa1 and MdMa11, and apple fruit malic acid accumulation.

vsiRNA18 derived from tobacco curly shoot virus can regulate virus infection in Nicotiana benthamiana.

Virus-derived small interfering RNAs (vsiRNAs) play important roles in regulating host endogenous gene expression to promote virus infection and induce RNA silencing to suppress virus infection. However, to date, how vsiRNAs affect geminivirus infection in host plants has been less studied. In this study, we found that tobacco curly shoot virus (TbCSV)-derived vsiRNA18 (TvsiRNA18) can regulate TbCSV infection in Nicotiana benthamiana plants. The virus-mediated small RNA expression system and stable transformation technique were used to clarify the molecular role of TvsiRNA18 in TbCSV infection. The results indicate that TvsiRNA18 can aggravate disease symptoms in these plants and enhance viral DNA accumulation. ATP-dependent RNA helicase (ATP-dRH) was proven to be a target of TvsiRNA18, and down-regulation of ATP-dRH in plants was shown to induce virus-like leaf curling symptoms and increase TbCSV infection. These results suggest that TvsiRNA18 is an important regulator of TbCSV infection by suppressing ATP-dRH expression. This is the first report to demonstrate that TbCSV-derived vsiRNA can target host endogenous genes to affect symptom development, which helps to reveal the molecular mechanism of symptom occurrence after the virus infects the host.

Identification of THSD7B and PRMT9 mutations as risk factors for familial lung adenocarcinoma: A case report.

RATIONALE: Lung tumors arise from the unrestrained malignant growth of pulmonary epithelial cells. Lung cancer cases include both small and non-small cell lung cancers, with lung adenocarcinoma (LUAD) accounting for roughly half of all non-small cell lung cancer cases. Research focused on familial cancers suggests that approximately 8% of lung cancer cases are linked to genetic susceptibility or heritability. The precise genetic factors that underlie the onset of lung cancer, however, remain to be firmly established. PATIENT CONCERNS: A 43-year-old presented with nodules in the lower left lung lobe. Following initial antibiotic treatment in a local hospital, these nodules remained present and the patient subsequently underwent the resection of the left lower lobe of the lung. The patient also had 4 family members with a history of LUAD. DIAGNOSIS: Immunohistochemical staining results including cytokeratin 7 (+), TTF-1 (+), new aspartic proteinase A (+), CK5/6 (-), P63 (-), and Ki-67 (5%+) were consistent with a diagnosis of LUAD. INTERVENTION: Whole exome sequencing analyses of 5 patients and 6 healthy family members were performed to explore potential mutations associated with familial LUAD. OUTCOMES: Whole exome sequencing was conducted, confirming that the proband and their 4 other family members with LUAD harbored heterozygous THSD7B (c.A4000G:p.S1334G) mutations and homozygous PRMT9 (c.G40T:p.G14C) mutations, as further confirmed via Sanger sequencing. These mutations were predicted to be deleterious using the SIFT, PolyPhen2, and MutationTaster algorithms. Protein structure analyses indicated that the mutation of the serine at amino acid position 1334 in THSD7B to a glycine would reduce the minimum free energy from 8.08 kcal/mol to 68.57 kcal/mol. The identified mutation in the PRMT9 mutation was not present in the predicted protein structure. I-Mutant2.0 predictions indicated that both of these mutations (THSD7B:p.S1334G and PRMT9: p.G14C) were predicted to reduce protein stability. LESSONS: Heterozygous THSD7B (c.A4000G:p.S1334G) and the homozygous PRMT9 (c.G40T:p.G14C) mutations were found to be linked to LUAD incidence in the analyzed family. Early analyses of these genetic loci and timely genetic counseling may provide benefits and aid in the early diagnosis of familial LUAD.

Mechanical performance of porous biomimetic intervertebral body fusion devices: an in vitro biomechanical study.

BACKGROUND: Degenerative disc disease is one of the most common ailments severely affecting the quality of life in elderly population. Cervical intervertebral body fusion devices are utilized to provide stability after surgical intervention for cervical pathology. In this study, we design a biomimetic porous spinal cage, and perform mechanical simulations to study its performances following American Society for Testing and Materials International (ASTM) standards before manufacturing to improve design process and decrease cost and consumption of material. METHODS: The biomimetic porous Ti-6Al-4 V interbody fusion devices were manufactured by selective laser melting (laser powder bed fusion: LPBF in ISO/ASTM 52900 standard) and subsequently post-processed by using hot isostatic pressing (HIP). Chemical composition, microstructure and the surface morphology were studied. Finite element analysis and in vitro biomechanical test were performed. FINDINGS: The post heat treatment can optimize its mechanical properties, as the stiffness of the cage decreases to reduce the stress shielding effect between two instrumented bodies. After the HIP treatment, the ductility and the fatigue performance are substantially improved. The use of HIP post-processing can be a necessity to improve the physical properties of customized additive manufacturing processed implants. INTERPRETATION: In conclusion, we have successfully designed a biomimetic porous intervertebral device. HIP post-treatment can improve the bulk material properties, optimize the device with reduced stiffness, decreased stress shielding effect, while still provide appropriate space for bone growth. CLINICAL SIGNIFICANCE: The biomechanical performance of 3-D printed biomimetic porous intervertebral device can be optimized. The ductility and the fatigue performance were substantially improved, the simultaneously decreased stiffness reduces the stress shielding effect between two instrumented bodies; while the biomimetic porous structures provide appropriate space for bone growth, which is important in the patients with osteoporosis.

Genome-wide identification, characterization and evolutionary dynamic of invertase gene family in apple, and revealing its roles in cold tolerance.

Invertases are ubiquitous enzymes that catalyze the unalterable cleavage of sucrose into glucose and fructose, and are crucially involved in plant growth, development and stress response. In this study, a total of 17 putative invertase genes, including 3 cell wall invertases, 3 vacuolar invertases, and 11 neutral invertases were identified in apple genome. Subcellular localization of MdNINV7 and MdNINV11 indicated that both invertases were located in the cytoplasm. Comprehensive analyses of physicochemical properties, chromosomal localization, genomic characterization, and gene evolution of MdINV family were conducted. Gene duplication revealed that whole-genome or segmental duplication and random duplication might have been the major driving force for MdINVs expansion. Selection index values, ω, showed strong evidence of positive selection signatures among the INV clusters. Gene expression analysis indicated that MdNINV1/3/6/7 members are crucially involved in fruit development and sugar accumulation. Similarly, expression profiles of MdCWINV1, MdVINV1, and MdNINV1/2/7/11 suggested their potential roles in response to cold stress. Furthermore, overexpression of MdNINV11 in apple calli at least in part promoted the expression of MdCBF1-5 and H2O2 detoxification in response to cold. Overall, our results will be useful for understanding the functions of MdINVs in the regulation of apple fruit development and cold stress response.

An urgent health problem of indoor air pollution: results from a 15-years carbon monoxide poisoning observed study in Jinan City.

Carbon monoxide (CO) poisoning is a public health concern in developing countries especially in China with a high disease burden. We aimed to focus on non-occupational CO poisoning caused by household coal heating secular trends based on registry data in Jinan, China, and we aim to provide further evidence and suggestions for public health policy. We analyzed the occurrence and development trend and assess the spatial-temporal epidemiological characteristics of non-occupational CO poisoning caused by household coal heating in Jinan between 2007 and 2021. Among total of 6588 CO poisoning, 5616 cases (85.25%) and 180 deaths caused by household coal heating was identified during study period. The cumulative incidence rate was 5.78 per 100,000 person-years and the mortality rate was 0.19 per 100,000 person-years. The incidence in urban areas (6.55 per 100,000 person-years) was higher than rural areas (5.04 per 100,000 person-years), and there was a statistical difference between urban and rural (P < 0.001) (P < 0.001). The poisoning time point mainly occurs in the sleep stage. In Jinan, socioeconomic status, accessibility to health services and rural status are determinants for CO poisoning incidence and mortality. Implementation of urban and rural central heating renovation is an effective way to further reduce the disease burden of CO poisoning in the future.

Macrophage migration inhibitory factor (MIF) inhibitor iSO-1 promotes staphylococcal protein A-induced osteogenic differentiation by inhibiting NF-κB signaling pathway.

BACKGROUND: Osteomyelitis is among the most difficult to treat diseases in the field of orthopedics, and there is a lack of effective treatment modalities. Exploring the mechanisms of its development is beneficial for finding molecular targets for treatment. Increasing evidence suggests that macrophage migration inhibitory factor (MIF), as a proinflammatory mediator, is not only involved in various pathophysiological processes of inflammation but also plays an important role in osteogenic differentiation, while its specific regulatory mechanism in osteomyelitis remains unclear. METHODS: In the present study, staphylococcal protein A (SPA)-treated rat bone marrow mesenchymal stem cells (rBMSCs) were used to construct cell models of osteomyelitis. Rat and cell models of osteomyelitis were used to validate the expression levels of MIF, and to further explore the regulatory mechanisms of the MIF inhibitor methyl ester of (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (iSO-1) and MIF knockdown on cell model of osteomyelitis toward osteogenic differentiation. RESULTS: We found that the expression level of MIF was upregulated in rat and cell models of osteomyelitis and subsequently demonstrated by the GSE30119 dataset that the expression level of MIF was also significantly upregulated in patients with osteomyelitis. Furthermore, SPA promotes MIF expression in rBMSCs while inhibiting the expression of osteogenic-related genes such as Runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), osteopontin (OPN) and collagen type-1 (COL-1) through activation of the nuclear factor kappa-B (NF-κB) pathway. In vivo, we further demonstrated that local injection of iSO-1 significantly increased the osteogenic activity in rat model of osteomyelitis. Importantly, we also demonstrated that MIF knockdown and the MIF inhibitor iSO-1 reversed the SPA-mediated inhibition of osteogenic differentiation of rBMSCs by inhibiting the activation of the NF-κB pathway, as evidenced by the upregulation of osteogenic-related gene expression and enhanced bone mineralization. CONCLUSION: ISO-1 and MIF knockdown can reverse the SPA-mediated inhibition of osteogenic differentiation in the rBMSCs model of osteomyelitis by inhibiting the NF-κB signaling pathway, providing a potential target for the treatment of osteomyelitis.

Calcyclin-binding protein-promoted degradation of MdFRUCTOKINASE2 regulates sugar homeostasis in apple.

Fructokinase (FRK) activates fructose through phosphorylation, which sends the activated fructose into primary metabolism and regulates fructose signaling capabilities in plants. The apple (Malus × domestica) FRK gene MdFRK2 shows especially high affinity to fructose, and its overexpression decreases fructose levels in the leaves of young plants. However, in the current study of mature plants, fruits of transgenic apple trees overexpressing MdFRK2 accumulated a higher level of fructose than wild-type (WT) fruits (at both young and mature stages). Transgenic apple trees with high mRNA MdFRK2 expression showed no significant differences in MdFRK2 protein abundance or FRK enzyme activity compared to WT in mature leaves, young fruits, and mature fruits. Immunoprecipitation-mass spectrometry analysis identified an skp1, cullin, F-box (SCF) E3 ubiquitin ligase, calcyclin-binding protein (CacyBP), that interacted with MdFRK2. RNA-sequencing analysis provided evidence for ubiquitin-mediated post-transcriptional regulation of MdFRK2 protein for the maintenance of fructose homeostasis in mature leaves and fruits. Further analyses suggested an MdCacyBP-MdFRK2 regulatory module in which MdCacyBP interacts with and ubiquitinates MdFRK2 to facilitate its degradation by the 26S proteasome, thus decreasing the FRK enzyme activity to elevate fructose concentration in transgenic apple trees. This result uncovered an important mechanism underlying plant fructose homeostasis in different organs through regulating MdFRK2 protein level via ubiquitination and degradation. Our study provides usable data for the future improvement of apple flavor and expands our understanding of the molecular mechanisms underlying plant fructose content and signaling regulation.

Establishing a glutamine metabolism-based model for predicting the prognosis of low-grade glioma.

Background: The natural history of patients with low-grade glioma (LGG) varies widely, but most patients eventually deteriorate, leading to poor prognostic outcomes. We aim to develop biological models that can accurately predict the outcome of LGG prognosis. Methods: Prognostic genes for glutamine metabolism were searched by univariate Cox regression, and molecular typing was constructed. Functional enrichment analysis was done to evaluate potential prognostic-related pathways by analyzing differential genes in different subtypes. Enrichment scores of specific gene sets in different subtypes were measured by gene set enrichment analysis. Different immune infiltration levels among subtypes were calculated using algorithms such as CIBERSORT and ESTIMATE. Gene expression levels of prognostic-related gene signatures of glutamine metabolism phenotypes were used to construct a RiskScore model. Receiver operating characteristic curve, decision curve and calibration curve analyses were used to evaluate the reliability and validity of the risk model. The decision tree model was used to determine the best predictor variable ultimately. Results: We found that C1 had the worst prognosis and the highest level of immune infiltration, among which the highest macrophage infiltration can be found in the M2 stage. Moreover, most of the pathways associated with tumor development, such as MYC_TARGETS_V1 and EPITHELIAL_MESENCHYMAL_TRANSITION, were significantly enriched in C1. The wild-type IDH and MGMT hypermethylation were the most abundant in C1. A five-gene risk model related to glutamine metabolism phenotype was established with good performance in both training and validation datasets. The final decision tree demonstrated the RiskScore model as the most significant predictor of prognostic outcomes in individuals with LGG. Conclusion: The RiskScore model related to glutamine metabolism can be an exceedingly accurate predictor for LGG patients, providing valuable suggestions for personalized treatment.

Multi-dimensional data transmission using inverse-designed silicon photonics and microcombs.

The use of optical interconnects has burgeoned as a promising technology that can address the limits of data transfer for future high-performance silicon chips. Recent pushes to enhance optical communication have focused on developing wavelength-division multiplexing technology, and new dimensions of data transfer will be paramount to fulfill the ever-growing need for speed. Here we demonstrate an integrated multi-dimensional communication scheme that combines wavelength- and mode- multiplexing on a silicon photonic circuit. Using foundry-compatible photonic inverse design and spectrally flattened microcombs, we demonstrate a 1.12-Tb/s natively error-free data transmission throughout a silicon nanophotonic waveguide. Furthermore, we implement inverse-designed surface-normal couplers to enable multimode optical transmission between separate silicon chips throughout a multimode-matched fibre. All the inverse-designed devices comply with the process design rules for standard silicon photonic foundries. Our approach is inherently scalable to a multiplicative enhancement over the state of the art silicon photonic transmitters.

I2/FeCl3-Catalyzed Domino Reaction of Aurones with Enamino Esters for the Synthesis of Highly Functionalized Pyrroles.

A novel and efficient I2/FeCl3-catalyzed domino reaction of aurones with enamino esters via Michael addition, iodination, intramolecular nucleophilic substitution, and spiro ring opening processes has been developed, affording a vast variety of polysubstituted pyrroles in moderate to excellent yields. This protocol features mild reaction conditions, broad substrate scope, high atom economy and efficiency, and feasibility for large-scale synthesis. A plausible mechanism for the pyrrole synthesis is proposed.

The clinical application of customized 3D-printed porous tantalum scaffolds combined with Masquelet's induced membrane technique to reconstruct infective segmental femoral defect.

PURPOSE: This study mainly exams a novel treatment for infective segmental femoral defect, and we combined the 3D printed porous tantalum prosthesis and Masquelet's induce membrane technique to reconstruct bone defect and discussed the clinical effect. METHOD: The clinical research included 9 observational cases series, as a permanently implantation, the customized 3D-printed scaffolds that connected with an anatomical plate was implanted into the bone defect segment after successful formation of induced membrane, the clinical effect was evaluated by radiological exams and Paley's bone union criteria. RESULT: The personalized 3D-printed porous tantalum was, respectively, manufactured and used in 9 consecutive patients to reconstruct the infective segmental bone defect of femur, the mean defect length was 16.1 ± 2.8 cm, the mean length of follow-up was 16.9 ± 4.0 months, after 2 stage operation, there was no deep infections, refractures, sensorimotor disorder, vascular injury, ankylosis and recurrence of infection occurred in all cases. postoperative radiological exams shown stable internal fixation and osseointegration, and all these results were invariable during the follow-up time in all cases. All patients significantly obtained deformity correction and length of limb. CONCLUSION: The customized 3D-printed porous tantalum prosthesis was an acceptable alternative treatment to the autogenous or allograft bone graft, the combination of the two techniques could achieve satisfactory reconstruct to infective broad bone defect in femur when other biological techniques were not suitable.

A new class of nucleating agents for poly(L-lactic acid): Environmentally-friendly metal salts with biomass-derived ligands and advanced nucleation ability.

Adding nucleating agents has been a successful strategy to boost the heat resistance of poly(L-lactic acid) (PLLA) by increasing the crystallinity. In this study, a new series of bio-based complexes as nucleating agents for PLLA, including twelve combinations of three eco-friendly metal ions (Zn, Mg, Ca) and four biomass-derived α-hydroxy acids, were successfully synthesized to respectively investigate the effects of metal ions as well as ligands on nucleation capacity of complexes. By investigating the non-isothermal and isothermal crystallization at 135 °C of PLLA with 0.3 wt% loading of complexes, both zinc and magnesium salts of L-mandelic acid showed excellent nucleation capacities. And magnesium L-mandelate performed better, raising the crystallinity of PLLA to 44.4 % as well as minimizing its crystallization half-time from 73 min to 2.7 min. The growth and denser distribution of PLLA spherulites on the salt surface were also observed by POM, reflecting epitaxial nucleation as the possible mechanism. A novel inspiration, utilizing VESTA software to simulate the crystal structure of zinc L-mandelate (Zn(L-MA)2), was proposed to determine the nucleation mechanism. Also, using polyethylene terephthalate (PET) as a test protocol, the rationality of the model could be approved by checking the fitness of nucleating prediction and experiment results.

Transcriptomics and metabolomics reveal effect of arbuscular mycorrhizal fungi on growth and development of apple plants.

Arbuscular mycorrhizal fungi (AMF) and plants form a symbiotic relationship that promotes plant growth and development. However, the regulatory mechanisms through which AMF promote plant growth and development are largely unexplored. In this study, the apple rootstock M26 was assessed physiologically, transcriptionally and metabolically when grown with and without AMF inoculation. AMF significantly promoted the number of lateral root (LR) increase and shoot elongation. Root transcriptomic and metabolic data showed that AMF promoted lateral root development mainly by affecting glucose metabolism, fatty acid metabolism, and hormone metabolism. Shoot transcriptomic and metabolic data showed that AMF promoted shoot elongation mainly by affecting hormone metabolism and the expression of genes associated with cell morphogenesis. To investigate whether shoot elongation is caused by root development, we analyzed the root/shoot dry weight ratio. There was a correlation between shoot growth and root development, but analysis of root and shoot metabolites showed that the regulation of AMF on plant shoot metabolites is independent of root growth. Our study bridged the gap in the field of growth and development related to AMF.

Malate metabolism mediated by the cytoplasmic malate dehydrogenase gene MdcyMDH affects sucrose synthesis in apple fruit.

The types and proportions of soluble sugar and organic acid in fruit significantly affect flavor quality. However, there are few reports on the crosstalk regulation between metabolism of organic acid and sugar in fruit. Here, we found that the overexpression of cytoplasmic malate dehydrogenase genes (MdcyMDHs) not only increased the malate content but also increased the sucrose concentration in transgenic apple calli and mature fruit. Enzyme activity assays indicated that the overexpression of MdcyMDH1 and MdcyMDH5 enhanced sucrose phosphate synthase (SPS) activity in transgenic materials. RNA-seq and expression analysis showed that the expression levels of SPS genes were up-regulated in MdcyMDH1-overexpressed apple fruit and MdcyMDH5-overexpressed apple calli. Further study showed that the inhibition of MdSPSB2 or MdSPSC2 expression in MdcyMDH1 transgenic fruit could reduce or eliminate, respectively, the positive effect of MdcyMDH1 on sucrose accumulation. Moreover, some starch cleavage-related genes (MdBAM6.1/6.2, MdBMY8.1/8.2, MdISA1) and the key gluconeogenesis-related phosphoenolpyruvate carboxykinase MdPEPCK1 gene were significantly up-regulated in the transcriptome differentially expressed genes of mature fruit overexpressing MdcyMDH1. These results indicate that alteration of malate metabolism mediated by MdcyMDH might regulate the expression of MdSPSs and SPS activity via affecting starch metabolism or gluconeogenesis, and thus accelerate sucrose synthesis and accumulation in fruit.

Coupling angle tolerance of the 850-nm single-mode VCSEL output collimated by lensed OM4-MMF or GI-SMF for a NRZ-OOK link.

By collimating the single-mode (SM) vertical-cavity surface-emitting laser (VCSEL) at 850 nm with either the OM4 multi-mode fiber (OM4-MMF) or the graded-index single-mode fiber (GI-SMF) with lensed end-face, the directly encoded non-return-to-zero on-off keying (NRZ-OOK) data transmission performance is characterized when tilting the coupling angle with respect to the surface normal of the SM-VCSEL. In comparison with the lensed OM4-MMF and lensed SMF coupling, the lensed OM4-MMF collimator shows a large coupling angle tolerance with the coupling efficiency only degraded by 5% when enlarging the tilted angle from 0° to 10°. In contrast, the lensed GI-SMF collimator attenuates the coupled SM-VCSEL output by more than 50% when tilting the coupling angle up to 10°. For the lensed OM4-MMF coupling, the receivable NRZ-OOK data rate in BtB and after 100-m OM4-MMF cases can achieve 50 Gbit/s with its corresponding BER degraded from 6.5 × 10-10 to 8.8 × 10-10 when enlarging its tilting angle ranged from 0° to 10°. By changing the collimator to the lensed SMF, the decoded BER significantly degrades from 5.8 × 10-5 to 1.2 × 10-1 when coupling and transmitting the NRZ-OOK data at 50 Gbit/s. Owing to the low coupling efficiency via the lensed SMF collimator, the error-free NRZ-OOK data rate under the lensed SMF coupling somewhat decreases to 35 Gbit/s in the BtB link and to 32 Gbit/s after the 100-m GI-SMF link with allowable coupling angle tilted from 0° to 4°. This work confirms the applicability of the lensed MMF or SMF collimator for coupling the SM-VCSEL output with a relatively large tolerance on the tilting angle with respect to the surface normal of the SM-VCSEL.

Bifunctional anti-PD-L1/TGF-ßRII agent SHR-1701 in advanced solid tumors: a dose-escalation, dose-expansion, and clinical-expansion phase 1 trial.

BACKGROUND: Dual inhibition of PD-1/PD-L1 and TGF-ß pathways is a rational therapeutic strategy for malignancies. SHR-1701 is a new bifunctional fusion protein composed of a monoclonal antibody against PD-L1 fused with the extracellular domain of TGF-ß receptor II. This first-in-human trial aimed to assess SHR-1701 in pretreated advanced solid tumors and find the population who could benefit from SHR-1701. METHODS: This was a dose-escalation, dose-expansion, and clinical-expansion phase 1 study. Dose escalation was initiated by accelerated titration (1 mg/kg q3w; intravenous infusion) and then switched to a 3+3 scheme (3, 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w), followed by dose expansion at 10, 20, and 30 mg/kg q3w and 30 mg/kg q2w. The primary endpoints of the dose-escalation and dose-expansion parts were the maximum tolerated dose and recommended phase 2 dose. In the clinical-expansion part, selected tumors were enrolled to receive SHR-1701 at the recommended dose, with a primary endpoint of confirmed objective response rate (ORR). RESULTS: In total, 171 patients were enrolled (dose-escalation: n=17; dose-expansion, n=33; clinical-expansion, n=121). In the dose-escalation part, no dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. SHR-1701 showed a linear dose-exposure relationship and the highest ORR at 30 mg/kg every 3 weeks, without obviously aggravated toxicities across doses in the dose-escalation and dose-expansion parts. Combined, 30 mg/kg every 3 weeks was determined as the recommended phase 2 dose. In the clinical-expansion part, SHR-1701 showed the most favorable efficacy in the gastric cancer cohort, with an ORR of 20.0% (7/35; 95% CI, 8.4-36.9) and a 12-month overall survival rate of 54.5% (95% CI, 29.5-73.9). Grade ≥3 treatment-related adverse events occurred in 37 of 171 patients (22%), mainly including increased gamma-glutamyltransferase (4%), increased aspartate aminotransferase (3%), anemia (3%), hyponatremia (3%), and rash (2%). Generally, patients with PD-L1 CPS ≥1 or pSMAD2 histochemical score ≥235 had numerically higher ORR. CONCLUSIONS: SHR-1701 showed an acceptable safety profile and encouraging antitumor activity in pretreated advanced solid tumors, especially in gastric cancer, establishing the foundation for further exploration. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03710265.