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De novo mutations arising on the paternal chromosome make the largest known contribution to autism risk, and correlate with paternal age at the time of conception. The recurrence risk for autism spectrum disorders is substantial, leading many families to decline future pregnancies, but the potential impact of assessing parental gonadal mosaicism has not been considered. We measured sperm mosaicism using deep-whole-genome sequencing, for variants both present in an offspring and evident only in father's sperm, and identified single-nucleotide, structural and short tandem-repeat variants. We found that mosaicism quantification can stratify autism spectrum disorders recurrence risk due to de novo mutations into a vast majority with near 0% recurrence and a small fraction with a substantially higher and quantifiable risk, and we identify novel mosaic variants at risk for transmission to a future offspring. This suggests, therefore, that genetic counseling would benefit from the addition of sperm mosaicism assessment.

BackgroundA better understanding of the blood supply of the femoral head is essential to guide therapeutic strategies for patients with femoral neck fractures. However, because of the limitations of conventional techniques, the precise distribution and characteristics of intraosseous arteries of the femoral head are not well displayed.Questions/purposesTo explore the characteristics and interconnections of the intraosseous vessel system between different areas of the femoral head and the possible blood supply compensatory mechanism after femoral neck fracture.MethodsThe three-dimensional (3-D) structures of the intraosseous blood supply in 30 uninjured normal human femoral heads were reconstructed using angiography methods and microCT scans. The data were imported in the AMIRA® and MIMICS® software programs to reconstruct and quantify the extra- and intraosseous arteries (diameter, length). In a separate experiment, we evaluated the residual blood supply of femoral heads in 27 patients with femoral neck fractures before surgery by analyzing digital subtraction angiography data; during the study period, this was performed on all patients in whom hip-preserving surgery was planned, rather than arthroplasty. The number of affected and unaffected subjects included in the three groups (superior, inferior, and anterior retinacular arteries) with different types of fractures (Garden Types I-IV) were recorded and analyzed (Fisher's exact test) to reflect the affected degrees of these three groups of retinacular arteries in patients after femoral neck fractures.ResultsThe main results of our cadaver study were: (1) the main blood supply sources of the femoral head were connected by three main network structures as a whole, and the epiphyseal arterial network is the most widely distributed and the primary network structure in the femoral head; (2) the main stems of the epiphyseal arteries which were located on the periphery of the intraosseous vascular system have fewer anastomoses than the network located in the central region; (3) compared with the round ligament artery and anterior retinacular artery, the inferior retinacular artery has a relatively large caliber. Digital subtraction angiography of the 27 patients with hip fractures indicated that the inferior retinacular arterial system had a high likelihood of being unaffected after femoral neck fracture (100% [14 of 14] in nondisplaced fractures and 60% [six of 10] in Garden Type III fractures).ConclusionsThe epiphyseal arterial network and inferior retinacular arterial system appear to be two important structures for maintaining the femoral head blood supply after femoral neck fracture. Increased efforts to protect these key structures during surgery, such as drilling and placing internal implants closer to the central region of the femoral head, might be helpful to reduce the effect of iatrogenic injury of the intraosseous vascular system.Clinical relevance3-D anatomic evidence of intraosseous arterial distribution of the femoral head and the high frequency with which the inferior retinacular arteries remained patent after femoral neck fracture lead us to consider the necessity of drilling and placing internal implants closer to the central region of the femoral head during surgery. Future controlled studies might evaluate this proposition.

While RNA therapeutics hold great promise for combating pancreatic ductal adenocarcinoma (PDAC), the limited therapy outcome due to the insufficient delivery efficiency of vehicles and inadequate innate therapeutic potency for single siRNA hinders the broader application. Herein, report bispecific, exosome‐mimetic lipid nanoparticles (EM‐LNPs) carrying high loads of siKras and siTP53, which can efficiently overcome layers of barriers to accumulate cytoplasm in vitro and in vivo and achieve synergistic treatment for PDAC tumors. EM‐LNPs inherit features of synthetic LNPs and the protein characteristics of exosomes with outer CD47 proteins, membrane‐inserted integrin α6β4, and connexin 43. The siRNAs‐loaded EM‐LNPs can efficiently evade the host immune clearance in the circulation, considerably accumulate and penetrate dense tumors, and simultaneously target EGFR/VEGF of PDAC cells, following leakage into the cytoplasm. The intracellular siKras and siTP53 achieved synergistic therapeutic effects for PDAC cells with as high as 20 times enhancement in vitro and 3.5 times increase in vivo, significantly suppressed xenograft PDAC tumors, considerably reduced lung metastasis, and vastly extended mice survival at a low injection dose. These results explore an approach for delivering multiple gene cargoes to dense PDAC tumors for synergistic therapeutics. [ABSTRACT FROM AUTHOR]

Circulating tumor cells (CTCs) have significant clinical value in early tumor detection, dynamic monitoring and immunotherapy. CTC detection stands out as a leading non-invasive approach for tumor diagnostics and therapeutics. However, the high heterogeneity of CTCs and the occurrence of epithelial-mesenchymal transition (EMT) during metastasis pose challenges to methods relying on EpCAM-positive enrichment. To address these limitations, a method based on negative enrichment of CTCs using specific leukocyte targets has been developed. In this study, aiming to overcome the low purity associated with immunomagnetic beads targeting solely the leukocyte common antigen CD45, we introduced CD66b-modified immunomagnetic beads. CD66b, a specific target for neutrophils with abundant residues, was chosen as a complementary approach. The process involved initial collection of nucleated cells from whole blood samples using density gradient centrifugation. Subsequently, magnetically labeled leukocytes were removed by magnetic field, enabling the capture of CTCs with higher sensitivity and purity while retaining their activity. Finally, we selected 20 clinical blood samples from patients with various cancers to validate the effectiveness of this strategy, providing a new generalized tool for the clinical detection of CTCs. [ABSTRACT FROM AUTHOR]