Melon seed extract protects against testis metal toxicity
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SEED-Selection enables high-efficiency enrichment of primary T cells edited at multiple loci
Engineering T cell specificity and function at multiple loci can generate more effective cellular therapies, but current manufacturing methods produce heterogenous mixtures of partially engineered cells. Here we develop a one-step process to enrich unlabeled cells containing knock-ins at multiple target loci using a family of repair templates named synthetic exon expression disruptors (SEEDs). SEEDs associate transgene integration with the disruption of a paired target endogenous surface protein while preserving target expression in nonmodified and partially edited cells to enable their removal (SEED-Selection). We design SEEDs to modify three critical loci encoding T cell specificity, coreceptor expression and major histocompatibility complex expression. The results demonstrate up to 98% purity after selection for individual modifications and up to 90% purity for six simultaneous edits (three knock-ins and three knockouts). This method is compatible with existing clinical manufacturing workflows and can be readily adapted to other loci to facilitate production of complex gene-edited cell therapies.
Iterative printing of bulk metal and polymer for additive manufacturing of multi-layer electronic circuits
In pursuing advancing additive manufacturing (AM) techniques for 3D objects, this study combines AM techniques for bulk metal and polymer on a single platform for one-stop printing of multilayer 3D electronic circuits with two novel aspects. The first innovation involves the embedded integration of electronic circuits by printing low-resistance electrical traces from bulk metal into polymer channels. Cross-section grinding results reveal (92 ± 5)% occupancy of electrically conductive traces in polymer channels despite the different thermal properties of the two materials. The second aspect encompasses the possibility of printing vertical bulk metal vias up to 10 mm in height with the potential for expansion, interconnecting electrically conductive traces embedded in different layers of the 3D object. The work provides comprehensive 3D printing design guidelines for successfully integrating fully embedded electrically conductive traces and the interconnecting vertical bulk metal vias. A smooth and continuous workflow is also introduced, enabling a single-run print of functional multilayer embedded 3D electronics. The design rules and the workflow facilitate the iterative printing of two distinct materials, each defined by unique printing temperatures and techniques. Observations indicate that conductive traces using molten metal microdroplets show a 12-fold reduction in resistance compared to nanoparticle ink-based methods, meaning this technique greatly complements multi-material additive manufacturing (MM-AM). The work presents insights into the behavior of molten metal microdroplets on a polymer substrate when printed through the MM-AM process. It explores their characteristics in two scenarios: When they are deposited side-by-side to form conductive traces and when they are deposited out-of-plane to create vertical bulk metal vias. The innovative application of MM-AM to produce multilayer embedded 3D electronics with bulk metal and polymer demonstrates significant potential for realizing the fabrication of free-form 3D electronics.
Resting-state fMRI reveals altered functional connectivity associated with resilience and susceptibility to chronic social defeat stress in mouse brain
Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How functional connectivity (FC) amongst interconnected, depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine FC between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of FC group differences with other stress-related limbic brain regions. SUS mice showed greater FC between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice but also indicated significantly decreased FC between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced FC between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater FC between the infralimbic prefrontal cortex and the nucleus accumbens shell compared to CON mice. These findings indicate unique differences in FC patterns in phenotypically distinct SUS and RES mice that could represent a neurobiological basis for depression, anxiety, and negative-coping behaviors that are associated with exposure to chronic stress.
Disrupting Amh and androgen signaling reveals their distinct roles in zebrafish gonadal differentiation and gametogenesis
Sex determination and differentiation in zebrafish involve a complex interaction of male and female-promoting factors. While Dmrt1 has been established as a critical male-promoting factor, the roles of Anti-Müllerian hormone (Amh) and androgen signaling remain less clear. This study employed an estrogen-deficient zebrafish model (cyp19a1a-/-) to dissect individual and combined roles of Amh and androgen receptor (Ar) signaling in gonadal differentiation and gametogenesis. Loss of amh, but not ar, could rescue all-male phenotype of cyp19a1a-/-, leading to female or intersex, confirming the role of Amh in promoting male differentiation. This rescue was recapitulated in bmpr2a-/- but not bmpr2b-/-, supporting Bmpr2a as the type II receptor for Amh in zebrafish. Interestingly, while disruption of amh or ar had delayed spermatogenesis, the double mutant (amh-/-;ar-/-) exhibited severely impaired spermatogenesis, highlighting their compensatory roles. While Amh deficiency led to testis hypertrophy, likely involving a compensatory increase in Ar signaling, Ar deficiency resulted in reduced hypertrophy in double mutant males. Furthermore, phenotype analysis of triple mutant (amh-/-;ar-/-;cyp19a1a-/-) provided evidence that Ar participated in early follicle development. This study provides novel insights into complex interplay between Amh and androgen signaling in zebrafish sex differentiation and gametogenesis, highlighting their distinct but cooperative roles in male development.
Composite vortex air laser
Structured air laser generated through establishing high-gain air media in a cavity-free scheme by intense ultrashort pulses is promising for optical manipulation and quantum communication at standoff distances. However, the mechanism how the orbital angular momentum (OAM) information can be entangled into strong-field-induced gain media is still controversial, making manipulation of the topological charges of structured air laser remain a challenge. Here, we report the realization of a composite vortex N2+ air laser with controllable OAM by manipulating the relative positions, polarization directions, and intensity ratio between a Gaussian-shaped pump and an external vortex seed. Numerical simulations reveal the essential role of the interference between self-seeded Gaussian-shaped and externally-seeded vortex lasing emissions in the topological charge transformation. Our findings not only shed light on the generation mechanism of vortex air lasers, but also open up avenues for quantum manipulation of structured light through strong-field laser ionization of molecules remotely.
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