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Lentiviral vector (LV)-based gene therapy holds promise for a broad range of diseases. Analyzing more than 280,000 vector integration sites (VISs) in 273 samples from 10 patients with X-linked severe combined immunodeficiency (SCID-X1), we discovered shared LV integrome signatures in 9 of 10 patients in relation to the genomics, epigenomics, and 3D structure of the human genome. VISs were enriched in the nuclear subcompartment A1 and integrated into super-enhancers close to nuclear pore complexes. These signatures were validated in T cells transduced with an LV encoding a CD19-specific chimeric antigen receptor. Intriguingly, the one patient whose VISs deviated from the identified integrome signatures had a distinct clinical course. Comparison of LV and gamma retrovirus integromes regarding their 3D genome signatures identified differences that might explain the lower risk of insertional mutagenesis in LV-based gene therapy. Our findings suggest that LV integrome signatures, shaped by common features such as genome organization, may affect the efficacy of LV-based cellular therapies.

Emerging 3D photonic circuits would greatly benefit from the ability to integrate skimming waveguides with low loss and controllable inscription depth into photonic circuits. These waveguides allow for the interaction of guiding light directly with external modulation signals and enable programmable photonic circuits. Here, we report the fabrication of a novel photonic-lattice-like skimming waveguide (PLLSW) using femtosecond laser writing. Our method enables fine control of cross-sectional symmetry and writing depth of waveguides, achieving a minimum depth of 1 μm and a low insertion loss of 1 dB. Based on the PLLSW, we demonstrate on-chip light modulation by designing an evanescent-field-type saturable absorber through the coupling of a carbon nanotube film with the PLLSW, which exhibits saturation intensity from 20 to 200 MW/cm2 through the balanced twin-detector measurement. The strong nonlinear optical response of the PLLSW-based saturable absorber is further exploited to drive a Q-switched pulse laser at 1550 nm based on a fiber laser cavity. Our work demonstrates an effective method to integrate nonlinear optical materials into a glass chip for all-optical switching based on 3D waveguides, which holds great potential for the construction of large-scale programmable photonic circuits in the future.

The creep deformation and damage mechanism of compacted graphite cast iron (CGI) with varying pearlite contents were studied at 450 °C, 500 °C, and 550 °C, with accompanying stress ranges from 40 MPa to 150 MPa. The creep deformation of CGI alloys presents obvious when the temperature exceeds 450 °C. The creep rate exponentially decreases with pearlite contents and the creep mechanism changes from dislocation slip to grain boundary sliding. There are (Ⅰ) intergranular and transgranular cracks, (Ⅱ) interfacial debonding between graphite and matrix, and (Ⅲ) pearlite morphologic transforming in the microstructure of CGI during the creep test. (Ⅰ) and (Ⅱ) are mainly caused by the creep stress and temperature, and (Ⅲ) may be related to plastic deformation. These cracks can interact with each other and accelerate the failure and fracture of materials.

BackgroundAllogeneic hematopoietic stem-cell transplantation for X-linked severe combined immunodeficiency (SCID-X1) often fails to reconstitute immunity associated with T cells, B cells, and natural killer (NK) cells when matched sibling donors are unavailable unless high-dose chemotherapy is given. In previous studies, autologous gene therapy with γ-retroviral vectors failed to reconstitute B-cell and NK-cell immunity and was complicated by vector-related leukemia.MethodsWe performed a dual-center, phase 1-2 safety and efficacy study of a lentiviral vector to transfer IL2RG complementary DNA to bone marrow stem cells after low-exposure, targeted busulfan conditioning in eight infants with newly diagnosed SCID-X1.ResultsEight infants with SCID-X1 were followed for a median of 16.4 months. Bone marrow harvest, busulfan conditioning, and cell infusion had no unexpected side effects. In seven infants, the numbers of CD3+, CD4+, and naive CD4+ T cells and NK cells normalized by 3 to 4 months after infusion and were accompanied by vector marking in T cells, B cells, NK cells, myeloid cells, and bone marrow progenitors. The eighth infant had an insufficient T-cell count initially, but T cells developed in this infant after a boost of gene-corrected cells without busulfan conditioning. Previous infections cleared in all infants, and all continued to grow normally. IgM levels normalized in seven of the eight infants, of whom four discontinued intravenous immune globulin supplementation; three of these four infants had a response to vaccines. Vector insertion-site analysis was performed in seven infants and showed polyclonal patterns without clonal dominance in all seven.ConclusionsLentiviral vector gene therapy combined with low-exposure, targeted busulfan conditioning in infants with newly diagnosed SCID-X1 had low-grade acute toxic effects and resulted in multilineage engraftment of transduced cells, reconstitution of functional T cells and B cells, and normalization of NK-cell counts during a median follow-up of 16 months. (Funded by the American Lebanese Syrian Associated Charities and others; LVXSCID-ND ClinicalTrials.gov number, NCT01512888.).

Breast cancer (BC) and benign breast lesions (BBLs) are common diseases in women worldwide. The gut microbiota plays a vital role in regulating breast diseases’ formation, progression, and therapy response. Hence, we explored the structure and function of gut microflora in patients with BC and BBLs. A cohort of 66 subjects was enrolled in the study. Twenty-six subjects had BC, 20 subjects had BBLs, and 20 matched healthy controls. High throughput 16S ribosomal RNA (16S rRNA) gene sequencing technology was used to determine the microbial community structure. Compared with healthy individuals, BC patients had significantly lower alpha diversity indices (Sobs index, p = 0.019; Chao1 index, p = 0.033). Sobs and Chao1 indices were also lower in patients with BBLs than healthy individuals, without statistical significance (p = 0.279, p = 0.314, respectively). Both unweighted and weighted UniFrac analysis showed that beta diversity differed significantly among the three groups (p = 3.376e–14, p < 0.001, respectively). Compared with healthy individuals, the levels of Porphyromonas and Peptoniphilus were higher in BC patients (p = 0.004, p = 0.007, respectively), whereas Escherichia and Lactobacillus were more enriched in the benign breast lesion group (p < 0.001, p = 0.011, respectively). Our study indicates that patients with BC and BBLs may undergo significant changes in intestinal microbiota. These findings can help elucidate the role of intestinal flora in BC and BBLs patients.

Al–Mn–Fe alloy was prepared by traditional casting, injection casting, and melt spinning. The effect of cooling rate on the microstructure of alloy was studied. Results show that the phases in the alloy are the same for the three methods, including quasicrystal icosahedral phase (I-phase), Al6Mn phase, and Al phase. With the increase in cooling rate, the morphology of the I-phase changed from long strips to short rods and gradually to a daisy shape, and the content of the I-phase increased from 28 to 70%. Meanwhile, the morphology of the Al6Mn phase in the alloy changed from long bars to short rods, and the content decreased from 45 to 20%. Meanwhile, the thermal expansion coefficient of the alloy in the injection casting state is significantly reduced by about 15% at all temperature stages compared with that in as-cast state, and the results show that an appropriate cooling rate can improve the microstructure and properties of the alloy.

In order to reduce the content of sulfur and ash in coal, improve the desulfurization and deashing rates, a combined experiment method of microwave magnetic separation-flotation was proposed for raw coal. The desulfurization and deashing rates of three experiment methods, namely, single magnetic separation, microwave magnetic separation, and microwave magnetic separation–flotation, were compared. Taking the microwave magnetic separation–flotation experiment method as the main line, the effects of the microwave irradiation time, microwave power, grinding time, magnetic field intensity, plate seam width, foaming agent dosage, collector dosage, and inhibitor dosage on desulfurization and deashing were discussed, and the mechanism of microwave irradiation on magnetic separation and flotation was revealed. The results show that under the conditions of a microwave irradiation time of 60 s, a microwave power of 80% of the rated power (800 W), a grinding time of 8 min, a plate seam width (the plate seam width of a magnetic separator sorting box) of 1 mm, a magnetic field intensity of 2.32 T, a foaming agent dosage of 90 g/t, a collector dosage of 2125 g/t, and an inhibitor dosage of 1500 g/t, the desulfurization and deashing effect is the best. The desulphurization rate is 76.51%, the sulfur removal rate of pyrite is 96.50%, and the deashing rate is 61.91%. Microwaves have the characteristic of selective heating, and the thermal conductivity of organic matter in coal is greater than that of mineral. Microwave irradiation can improve the reactivity of pyrite in coal, pyrolyze pyrite into high-magnetic pyrite, improve the magnetic properties, and improve the magnetic separation effect. Therefore, microwave irradiation plays a role in promoting magnetic separation. Through microwave irradiation, the positive and negative charges in coal molecules constantly vibrate and create friction under the action of an electric field force, and the thermal action generated by this vibration and friction process affects the structural changes in oxygen-containing functional groups in coal. With the increase in the irradiation time and power, the hydrophilic functional groups of –OH and –COOH decrease and the hydrophilicity decreases. Microwave heating evaporates the water in the pores of coal samples and weakens surface hydration. At the same time, microwave irradiation destroys the structure of coal and impurity minerals, produces cracks at the junction, increases the surface area of coal to a certain extent, enhances the hydrophobicity, and then improves the effect of flotation desulfurization and deashing. Therefore, after the microwave irradiation of raw coal, the magnetic separation effect is enhanced, and the flotation desulfurization effect is also enhanced. [ABSTRACT FROM AUTHOR]