A Compact Base Editor Rescues AATD-associated Liver and Lung Disease in Mouse Models.

Alpha-1 antitrypsin deficiency (AATD) is commonly caused by a G-to-A mutation in the SERPINA1 gene (the PiZ mutation). The mutant PiZ AAT protein is sequestered in hepatocytes, causing lung emphysema due to insufficient AAT protein to inhibit neutrophil elastase in the lung. Here, we show that a compact adenine base editor (ABE) with an evolved Cas9 nickase derived from Neisseria meningitidis (eNme2.

Prime assembly with linear DNA donors enables large genomic insertions.

Targeted insertion of large DNA fragments has promising applications for genome engineering and gene therapy. Twin prime editing (PE) guide RNAs (pegRNAs) have enabled relatively large insertions, but the efficiency remains low for insertions greater than 400 base pairs. Here we describe a Prime Assembly (PA) approach for the insertion of large DNA donor fragments, whose ends are designed to overlap with the flaps generated by twinPE.

Neurexin-3a IgG-mediated autoimmune encephalitis: a case report and literature review.

We summarized the clinical manifestations, auxiliary examinations, treatment, and prognostic characteristics of a patient with neurexin-3a IgG-mediated autoimmune encephalitis. On March 2, 2024, a 43-year-old male patient was admitted to the Second Hospital of Shandong University and had prodromal symptoms of infection before the onset of encephalitis. The main manifestations were episodic loss of consciousness, eyes turned upward to the right, clenched teeth, bleeding from tongue bite, and limb twitching.

Distinctive lymph node metastasis characteristics and predictive model for young oral squamous cell carcinoma patients under 30.

Occult cervical lymph node metastasis (OCLNM) significantly influences clinical management and prognosis in young oral squamous cell carcinoma (OSCC) patients under 30 years old, who demonstrate distinct disease features compared to older cohorts. This retrospective study analyzed 66 OSCC patients under 30 treated between 2012 and 2024 to identify risk factors for cervical lymph node metastasis (CLNM) and develop a predictive model. Among the cohort, 36.

Association between systemic immune inflammation index and serum testosterone and free testosterone in middle-aged and elderly men.

Background: Chronic inflammation is a pervasive feature of aging and may be associated with testosterone in middle-aged and older men. Systemic immune-inflammation index (SII) is a novel inflammatory biomarker. We aimed to assess the association between SII and serum testosterone and free testosterone (FT) in middle-aged and older men.

Inferring kinase-phosphosite regulation from phosphoproteome-enriched cancer multi-omics datasets.

Phosphorylation in eukaryotic cells plays a key role in regulating cell signaling and disease progression. Despite the ability to detect thousands of phosphosites in a single experiment using high-throughput technologies, the kinases responsible for regulating these sites are largely unidentified. To solve this, we collected the quantitative data at the transcriptional, protein, and phosphorylation levels of 10 159 samples from 23 tumor datasets and 15 adjacent normal tissue datasets.

Changes in root-associated bacterial communities across growth stages of salt-tolerant and salt-sensitive rice grown in coastal saline-alkali soils.

In this study, the root-associated bacterial communities of salt-tolerant and salt-sensitive rice grown in coastal saline-alkali soils were characterized at three major growth stages (jointing, heading and maturity) using Illumina MiSeq sequencing. The results showed that the growth stage had a stronger influence on endophytic bacterial diversity than the genotype, with diversity decreasing as growth progressed. However, the rhizospheric bacterial diversity was minimally affected by both growth stage and genotype.

Unique clinical features and prognostic risk factors of oral squamous cell carcinoma in patients under 30 years old.

Background: Individuals under 30 years old with oral squamous cell carcinoma (OSCC) are a relatively rare subgroup but require attention. However, literature on the clinicopathological characteristics of OSCC patients under 30 is currently lacking.

Methods: A total of 66 OSCC patients under 30 were included in this study.

Tailoring femtosecond LSP resonance and lifetime in a nanoresonator via phase retardation.

The manipulation of femtosecond plasmon resonance and lifetime in a nanoantenna is crucial for the realization of integrated and miniaturized plasmonic circuits. Here, we have used FDTD simulations to study the plasmonic resonance and lifetime variation of the far-end (P) and near-end (P) hotspots of size-gradient nanoresonators. We found that the near-field spectrum of P is red-shifted compared to P due to the phase retardation effect.

Rational Design of Enhanced Nme2Cas9 and Nme2Cas9 Nucleases and Base Editors.

CRISPR-Cas genome editing tools enable precise, RNA-guided modification of genomes within living cells. The most clinically advanced genome editors are Cas9 nucleases, but many nuclease technologies provide only limited control over genome editing outcomes. Adenine base editors (ABEs) and cytosine base editors (CBEs) enable precise and efficient nucleotide conversions of A:T-to-G:C and C:G-to-T:A base pairs, respectively.

Age-related testosterone decline: mechanisms and intervention strategies.

Contemporary societies exhibit delayed reproductive age and increased life expectancy. While the male reproductive system demonstrates relatively delayed aging compared to that of females, increasing age substantially impacts its function. A characteristic manifestation is age-induced testosterone decline.

Functional sufficient dimension reduction through information maximization with application to classification.

Considering the case where the response variable is a categorical variable and the predictor is a random function, two novel functional sufficient dimensional reduction (FSDR) methods are proposed based on mutual information and square loss mutual information. Compared to the classical FSDR methods, such as functional sliced inverse regression and functional sliced average variance estimation, the proposed methods are appealing because they are capable of estimating multiple effective dimension reduction directions in the case of a relatively small number of categories, especially for the binary response. Moreover, the proposed methods do not require the restrictive linear conditional mean assumption and the constant covariance assumption.

Extracellular vesicles in anti-tumor drug resistance: Mechanisms and therapeutic prospects.

Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug efflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME).

[Analysis of traditional Chinese medicine diagnosis and treatment for erectile dysfunction related to COVID-19 infection].

The incidence of erectile dysfunction (ED) has been reported to increase after COVID-19 infection, and it is common in COVID-19 patients during recovery. This paper presents a summary of the latest research progress on COVID-19-induced ED and explores the traditional Chinese medicine (TCM) diagnosis and treatment approach based on TCM theory and clinical experience. COVID-19 infection may lead to ED through endothelial dysfunction, testicular injury, hormonal imbalance, and psychological factors.

Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope.

Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we engineer Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first use domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex.

Prime Editing by Lipid Nanoparticle Co-delivery of Chemically Modified pegRNA and Prime Editor mRNA.

Prime editing has gained significant attention as a next-generation gene editing technology, owing to its unique advantages. However, realizing its potential requires effective delivery strategies. While adeno-associated virus (AAV) has been employed for delivery of prime editors in research settings, it presents inherent limitations related to vector size, ongoing expression, and inability to re-dose patients.

The distribution profiles of tetracycline resistance genes in rice: Comparisons using four genotypes.

The potential transmission of antibiotic resistance genes (ARGs) from the rhizosphere to plants and humans poses a significant concern. This study aims to investigate the distribution of tetracycline resistance genes (TRGs) in rice using four genotypes and identify the primary source of TRGs in grains. Quantitative polymerase chain reaction (qPCR) was employed to determine the abundance of seven TRGs and intI1 in four rice varieties and three partitions during the jointing and heading stages, respectively.

Targeted genome editing with a DNA-dependent DNA polymerase and exogenous DNA-containing templates.

Reverse transcriptases, used in prime editing systems, exhibit lower fidelity, processivity and dNTP affinity than many DNA-dependent DNA polymerases. We report that a DNA-dependent DNA polymerase (phi29), untethered from Cas9, enables editing from a synthetic, end-stabilized DNA-containing template at up to 60% efficiency in human cells. Compared to prime editing, DNA polymerase editing avoids autoinhibitory intramolecular base pairing of the template, facilitates template synthesis and supports larger insertions (>100 nucleotides).

Gypenoside Pretreatment Alleviates the Cerebral Ischemia Injury via Inhibiting the Microglia-Mediated Neuroinflammation.

Neuroinflammation is closely related to prognosis in ischemic stroke. Microglia are the main immune cells in the nervous system. Under physiological conditions, microglia participate in clearance of dead cells, synapse pruning and regulation of neuronal circuits to maintain the overall health of the nervous system.

Engineering Nme2Cas9 Adenine Base Editors with Improved Activity and Targeting Scope.

Nme2Cas9 has been established as a genome editing platform with compact size, high accuracy, and broad targeting range, including single-AAV-deliverable adenine base editors. Here, we have engineered Nme2Cas9 to further increase the activity and targeting scope of compact Nme2Cas9 base editors. We first used domain insertion to position the deaminase domain nearer the displaced DNA strand in the target-bound complex.

Unsupervised Visual Representation Learning via Multi-Dimensional Relationship Alignment.

Recently, contrastive learning based on augmentation invariance and instance discrimination has made great achievements, owing to its excellent ability to learn beneficial representations without any manual annotations. However, the natural similarity among instances conflicts with instance discrimination which treats each instance as a unique individual. In order to explore the natural relationship among instances and integrate it into contrastive learning, we propose a novel approach in this paper, Relationship Alignment (RA for abbreviation), which forces different augmented views of current batch instances to main a consistent relationship with other instances.

Color Tunable, Lithography-Free Refractory Metal-Oxide Metacoatings with a Graded Refractive Index Profile.

The refractory metal-oxide semiconductors are an overlooked platform for nanophononics that offer alloys with high melting points and tunable optical constants through stoichiometry changes and ion intercalation. We show that these semiconductors can form metamaterial coatings (metacoatings) made from a set of highly subwavelength, periodic metal-oxide layers (≤20 nm) with a varying and graded refractive index profile that includes a combination of high and low refractive indices and plasmonic layers. These metacoatings exhibit vibrant, structural color arising from the periodic index profile that can be tuned across the visible spectrum, over ultralarge lateral areas through bottom-up thermal annealing techniques.

dSCOPE: a software to detect sequences critical for liquid-liquid phase separation.

Membrane-based cells are the fundamental structural and functional units of organisms, while evidences demonstrate that liquid-liquid phase separation (LLPS) is associated with the formation of membraneless organelles, such as P-bodies, nucleoli and stress granules. Many studies have been undertaken to explore the functions of protein phase separation (PS), but these studies lacked an effective tool to identify the sequence segments that critical for LLPS. In this study, we presented a novel software called dSCOPE (http://dscope.