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Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.

Abstract Background The Blau syndrome (MIM 186580), an autosomal dominant granulomatous disease, was previously mapped to chromosome 16p12-q21. However, inconsistent physical maps of the region and consequently an unknown order of microsatellite markers, hampered us from further refining the genetic locus for the Blau syndrome. To address this problem, we constructed our own high-resolution physical map for the Blau susceptibility region. Results We generated a high-resolution physical map that provides more than 90% coverage of a refined Blau susceptibility region. The map consists of four contigs of sequence tagged site-based bacterial artificial chromosomes with a total of 124 bacterial artificial chromosomes, and spans approximately 7.5 Mbp; however, three gaps still exist in this map with sizes of 425, 530 and 375 kbp, respectively, estimated from radiation hybrid mapping. Conclusions Our high-resolution map will assist genetic studies of loci in the interval from D16S3080, near D16S409, and D16S408 (16q12.1 to 16q13).

In the current research, the dynamic behavior of the spherical nanoshell subjected to a moving harmonic load in hygro-thermo environment is examined for the first time. A size-dependent nonlocal shell theory is dedicated to ponder the nonlocality. The first-order shear deformation theory is dedicated to inquire the shear impacts along with the thickness of the shell. To ponder the effects of the thermal and moisture conditions on the dynamic responses of the nanoshell, we apply the nonlinear relations for temperature and moisture fields. In the current study, it is assumed that the nanoshell is subjected to a moving harmonic load which moves the upper surface of the nanoshell with a certain velocity along the path $ {x_2} = \frac{b}{2} $ x 2 = b 2 . Hamilton's axiom is dedicated to achieve the governing equations of motion. Then, the Navier solution technique is dedicated to derive the dynamic responses of the nanoshell with simply-supported boundary conditions. The impacts of several parameters are examined on the dynamic behavior of the nanoshell. [ABSTRACT FROM AUTHOR]

Aqueous two‐phase emulsion (ATPE)‐based bioinks, a creative innovation for bioprinting, enable the fabrication of complex 3D cell‐laden hydrogels with macroporous structure, which promote cellular activities within the scaffold. However, these bioinks intrinsically lack stability and specific biofunctionality, potentially limiting their application for targeted tissue engineering. This study proposes a new perspective by introducing less than 0.1% phosphorylated cellulose nanofibrils (pCNF), a 1D nanofibril top‐down produced from natural biomasses, into a dextran/methacrylated gelatin (GelMA)‐based ATPE system for extrusion‐based bioprinting of preosteoblastic cells, aiming to fabricate macroporous hydrogels with osteogenic differentiation potential. The pCNF that is selectively partitioned in the GelMA phase can not only improve the emulsion stability and alter the rheological behaviors of the ATPE‐based bioink, but also enhance the damping capacity and mineralization ability of the crosslinked hydrogels. Furthermore, macroporous hydrogels with pCNF demonstrate increased cell activity and higher viability in post‐printing, along with higher alkaline phosphatase activity and osteoblastic gene expression. Importantly, the organized interfaces within the hydrogel facilitate the formation of macroscopic biomineralized nodules in vitro. The incorporation of multifunctional pCNF in the ATPE system significantly boosts the physiochemical and biological performance of the macropore‐forming bioink, transforming them into a suitable platform for engineering in vitro bone models. [ABSTRACT FROM AUTHOR]

The design of lignin nanostructures where interfacial interactions enable enhanced entanglement of colloidal networks can broaden their applications in hydrogel‐based materials and light‐based 3D printing. Herein, an approach for fabricating surface‐active dendritic colloidal microparticles (DCMs) characterized by fibrous structures using nanostructured allylated lignin is proposed for the development of lignin‐based photocurable resins. With allyl‐terminated surface functionality of 0.61 mmol g−1, the entanglement between lignin‐DCM fibrils with a size of 1.4 µm successfully produces only lignin‐based hydrogels with structural integrity through photo‐crosslinking. The colloidal network of lignin dendricolloids reinforces the poly(ethylene glycol) (PEG) hydrogels during a digital light processing (DLP) 3D printing process by generating bicontinuous morphologies, resulting in six‐fold increases in toughness values with respect to the neat PEG hydrogel. The dual effectiveness of photoabsorption and free‐radical reactivity of lignin‐DCMs allow the light‐patterning of rather dilute PEG hydrogels (5–10%) with high geometric fidelity and structural complexity via DLP 3D printing. This study demonstrates a green and effective strategy for the design of 1D lignin‐DCMs that increases the versatility of the nanostructured biopolymer, opening up numerous opportunities for formulating functional hydrogels with robust structure‐property correlations. [ABSTRACT FROM AUTHOR]

Diabetic wound healing is a serious, complex, and chronic process; one current promising and focusing technology in this area is stem cell treatment. Here, novel porous microneedle (MN) arrays is fabricated, which can highly mimetic stem cell niches, through template filling, and particle etching method. The human adipose‐derived stem cells (ADSCs) are encapsulated in Matrigel then loaded into the porous MN arrays by post‐perfusion. Because of the extracellular matrix‐mimicking, the biocompatible Matrigel offers a bionic microenvironment of stem cell nest suitable for growth. Benefiting from the numerous pore structures of MNs, the loaded ADSCs have enough space to fully absorb nutrients, proliferate greatly and exhibit prompted function. In addition, the cell‐loaded MN arrays have enough mechanical strength to penetrate the skin, allowing the ADSCs to get into the deep wound areas. Based on these features, the performance of the resultant MN arrays in promoting tissue regeneration is demonstrated, collagen deposition and angiogenesis in diabetes wounds of rat models. Thus, it is believe that the bioinspired porous MNs can act as excellent stem cell scaffolds and will find many practical values in clinic wound healing. [ABSTRACT FROM AUTHOR]

The present study focuses on enhancing the thermomechanical properties of poly(methyl methacrylate) (PMMA), a transparent and biocompatible polymer known for its high strength but limited toughness. The approach involves the development of PMMA/cellulose nanocrystals (CNCs) composites. To improve the interfacial compatibility between PMMA and CNCs, a two‐step process is employed. Initially, the CNCs undergo oxidation using sodium periodate, followed by the introduction of amino groups through reductive amination. The aminated CNCs are then covalently bonded to PMMA via an amidation reaction using the "grafting onto" approach. Subsequently, the grafted CNCs are incorporated into the PMMA matrix using the solvent casting method. The resulting composites are extruded into filaments. Elemental composition analysis confirms CNC modification, revealing the presence of 1.6% nitrogen. The modified CNCs exhibit a higher degradation temperature than unmodified CNCs, showing a 50°C increase. The composites' dynamic mechanical analysis (DMA) reveals a 20% improvement in storage modulus (E′) upon incorporating 1.5% of the grafted CNCs into the PMMA matrix. This enhancement is attributed to the formation of co‐continuous phases in the composite structure. [ABSTRACT FROM AUTHOR]