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Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths, warranting better therapies. Restoration of tumor-suppressive microRNAs depleted in hepatocellular carcinoma represents a new therapeutic strategy. Herein, we sought to identify a potent microRNA (miRNA) agent that could alleviate HCC tumor burden and improve survival. Among a collection of bioengineered noncoding RNA molecules produced through bacterial fermentation, we identified let-7c agent as the most potent inhibitor of HCC cell viability. Bioengineered let-7c selectively modulated target gene expression (Lin-28 homolog B [LIN28B], AT-rich interactive domain-containing protein 3B [ARID3B], B cell lymphoma-extra large [Bcl-xl], and c-Myc) in HCC cells, and consequently induced apoptosis and inhibited tumorsphere growth. When formulated with liposomal-branched polyethylenimine polyplex, bioengineered let-7c exhibited serum stability up to 24 h. Furthermore, liposomal polyplex-formulated let-7c could effectively reduce tumor burden and progression in orthotopic HCC mouse models, while linear polyethyleneimine-formulated let-7c to a lower degree, as revealed by live animal and ex vivo tissue imaging studies. This was also supported by reduced serum α-fetoprotein and bilirubin levels in let-7c-treated mice. In addition, lipopolyplex-formulated let-7c extended overall survival of HCC tumor-bearing mice and elicited no or minimal immune responses in healthy immunocompetent mice and human peripheral blood mononuclear cells. These results demonstrate that bioengineered let-7c is a promising molecule for advanced HCC therapy, and liposomal polyplex is a superior modality for in vivo RNA delivery.

Our recent studies have revealed that microRNA-1291 (miR-1291) is downregulated in pancreatic cancer (PC) specimens and restoration of miR-1291 inhibits tumorigenesis of PC cells. This study is to assess the efficacy and underlying mechanism of our bioengineered miR-1291 prodrug monotherapy and combined treatment with chemotherapy. AT-rich interacting domain protein 3B (ARID3B) was verified as a new target for miR-1291, and miR-1291 prodrug was processed to mature miR-1291 in PC cells which surprisingly upregulated ARID3B mRNA and protein levels. Co-administration of miR-1291 with gemcitabine plus nab-paclitaxel (Gem-nP) largely increased the levels of apoptosis, DNA damage and mitotic arrest in PC cells, compared to mono-drug treatment. Consequently, miR-1291 prodrug improved cell sensitivity to Gem-nP. Furthermore, systemic administration of in vivo-jetPEI-formulated miR-1291 prodrug suppressed tumor growth in both PANC-1 xenograft and PC patients derived xenograft (PDX) mouse models to comparable degrees as Gem-nP alone, while combination treatment reduced tumor growth more ubiquitously and to the greatest degrees (70-90%), compared to monotherapy. All treatments were well tolerated in mice. In conclusion, biologic miR-1291 prodrug has therapeutic potential as a monotherapy for PC, and a sensitizing agent to chemotherapy.

Despite decades of research, the fundamental question of structure and morphology of the poly(3,‐4‐ethylenedioxythiophene):poly(styrene sulfonate) complex (PEDT: PSS) electrically conducting polymer remains open. Here, through a systematic study of the polymerization of 3,4‐ethylenedioxythiophene (EDT) on two series of sulfonated polystyrenes, i.e., PS‐co‐SSH and PS‐co‐SSNa, with per cent sulfonation 24 ≲ x ≲ 100, this study shows that the substrate polyelectrolyte not only affords charge compensation and processability, but also templates the morphology of the growing PEDT chain—whether extended, coiled or collapsed. This determines the electrical, electronic and optical properties of the resultant PEDT: PSS interpolyelectrolyte complexes, including their work function. This study calls this the Polyelectrolyte Template model. The PEDT: PSS complex retains memory of its polymerization morphology even after subsequent ion‐exchange, for example, to the same acid form. Electrical conductivity decreases sharply with decreasing x, and depends on whether the polymerization is templated with the H+ or Na+ form of the polyelectrolyte. The work function is less sensitive to x, but exhibits a transition from low to high work function (5.2–5.3 eV) when x exceeds a threshold, which indicates formation of a polar surface driven by molecular‐scale segregation of the PSS counteranion. This surface segregation also affects the ability of these complexes to inject holes into very large‐ionization‐energy semiconductors. [ABSTRACT FROM AUTHOR]

As the scale of federated learning expands, solving the Non‐IID data problem of federated learning has become a key challenge of interest. Most existing solutions generally aim to solve the overall performance improvement of all clients; however, the overall performance improvement often sacrifices the performance of certain clients, such as clients with less data. Ignoring fairness may greatly reduce the willingness of some clients to participate in federated learning. In order to solve the above problem, the authors propose Ada‐FFL, an adaptive fairness federated aggregation learning algorithm, which can dynamically adjust the fairness coefficient according to the update of the local models, ensuring the convergence performance of the global model and the fairness between federated learning clients. By integrating coarse‐grained and fine‐grained equity solutions, the authors evaluate the deviation of local models by considering both global equity and individual equity, then the weight ratio will be dynamically allocated for each client based on the evaluated deviation value, which can ensure that the update differences of local models are fully considered in each round of training. Finally, by combining a regularisation term to limit the local model update to be closer to the global model, the sensitivity of the model to input perturbations can be reduced, and the generalisation ability of the global model can be improved. Through numerous experiments on several federal data sets, the authors show that our method has more advantages in convergence effect and fairness than the existing baselines. [ABSTRACT FROM AUTHOR]

Background For adolescents, abnormal dipping patterns in blood pressure (BP) are associated with early-onset organ damage and a higher risk of cardiovascular disorders in adulthood. Obesity is one of the most common reasons for abnormal BP dipping in young people. However, it is unknown whether the severity of obesity is associated with BP dipping status and whether this association is sex-dependent. Methods 499 participants between 12 and 17 years old with overweight or obesity underwent ambulatory blood pressure monitoring (ABPM) between April 2018 and January 2019 in Beijing and Baoding. Participants were grouped by body mass index (BMI) into overweight (BMI 85th–95th percentile), obese (BMI≥95th percentile) and severely obese (BMI≥120% of 95th percentile or ≥35 kg/m2) groups. Non-dipping was defined as a<10% reduction in BP from day to night. The interaction effect between sex and obesity degree was also analyzed. Results 326 boys and 173 girls were included, of whom 130 were overweight, 189 were obese, and 180 were severely obese. Girls with severe obesity had a higher prevalence of non-dipping, but boys showed no significant differences in BP dipping status between obesity categories. In addition, as obesity severity went up, a more evident increase in night-time SBP was observed in girls than in boys. Conclusions Severely obese is associated with a higher prevalence of non-BP dipping patterns in girls than in boys, which suggests that the relationship between the severity of obesity and BP dipping status might be sex-specific. [ABSTRACT FROM AUTHOR]

Icosahedral B12 serves as a fundamental building block for a variety of boron allotropes and plays a crucial role in enhancing the stability of fullerene-like boron nanoclusters. However, progress in the development of two-dimensional (2D) functional assemblies made from icosahedral B12 has been limited. In this context, we propose a 2D semiconducting boron allotrope (h-B12) using icosahedral B12 as a building block. This structure features a stable honeycomb lattice, with its unit cell comprising two mirror-symmetric icosahedral B12 clusters. The results of first-principles calculations indicate that the band structure exhibits Dirac cones and a relatively high group velocity, similar to graphene. Additionally, it is found to be a material with a negative Poisson's ratio and a relatively low Young's modulus. Finally, our calculations reveal that the zigzag nanoribbon constructed from h-B12 displays prominent edge states at both edges, indicating that this structure represents a potential topological electronic material. Our findings shed light on the design and construction of nano-electronic materials via cluster assembly. [ABSTRACT FROM AUTHOR]

Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biologic ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher level expression (40%-80% of total RNAs) of recombinant ncRNAs in bacteria and gave an 80% success rate (33 of 42 ncRNAs). New FPLC and spin-column based methods were also developed for large- and small-scale purification of milligrams and micrograms of recombinant ncRNAs from half liter and milliliters of bacterial culture, respectively. We then used two bioengineered nCAR/miRNAs to demonstrate the selective release of target miRNAs into human cells, which were revealed to be Dicer dependent (miR-34a-5p) or independent (miR-124a-3p), and subsequent changes of miRNome and transcriptome profiles. miRNA enrichment analyses of altered transcriptome confirmed the specificity of nCAR/miRNAs in target gene regulation. Furthermore, nCAR assembled miR-34a-5p and miR-124-3p were active in suppressing human lung carcinoma cell proliferation through modulation of target gene expression (e.g., cMET and CDK6 for miR-34a-5p; STAT3 and ABCC4 for miR-124-3p). In addition, bioengineered miRNA molecules were effective in controlling metastatic lung xenograft progression, as demonstrated by live animal and ex vivo lung tissue bioluminescent imaging as well as histopathological examination. This novel ncRNA bioengineering platform can be easily adapted to produce various ncRNA molecules, and biologic ncRNAs hold the promise as new cancer therapeutics.

Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biologic ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher level expression (40%-80% of total RNAs) of recombinant ncRNAs in bacteria and gave an 80% success rate (33 of 42 ncRNAs). New FPLC and spin-column based methods were also developed for large- and small-scale purification of milligrams and micrograms of recombinant ncRNAs from half liter and milliliters of bacterial culture, respectively. We then used two bioengineered nCAR/miRNAs to demonstrate the selective release of target miRNAs into human cells, which were revealed to be Dicer dependent (miR-34a-5p) or independent (miR-124a-3p), and subsequent changes of miRNome and transcriptome profiles. miRNA enrichment analyses of altered transcriptome confirmed the specificity of nCAR/miRNAs in target gene regulation. Furthermore, nCAR assembled miR-34a-5p and miR-124-3p were active in suppressing human lung carcinoma cell proliferation through modulation of target gene expression (e.g., cMET and CDK6 for miR-34a-5p; STAT3 and ABCC4 for miR-124-3p). In addition, bioengineered miRNA molecules were effective in controlling metastatic lung xenograft progression, as demonstrated by live animal and ex vivo lung tissue bioluminescent imaging as well as histopathological examination. This novel ncRNA bioengineering platform can be easily adapted to produce various ncRNA molecules, and biologic ncRNAs hold the promise as new cancer therapeutics.