Neural correlates of novelty detection in the primary auditory cortex of behaving monkeys.

The neural mechanisms underlying novelty detection are not well understood, especially in relation to behavior. Here, we present single-unit responses from the primary auditory cortex (A1) from two monkeys trained to detect deviant tones amid repetitive ones. Results show that monkeys can detect deviant sounds, and there is a strong correlation between late neuronal responses (250-350 ms after deviant onset) and the monkeys' perceptual decisions. The magnitude and timing of both neuronal and behavioral responses are increased by larger frequency differences between the deviant and standard tones and by increasing the number of standard tones preceding the deviant. This suggests that A1 neurons encode novelty detection in behaving monkeys, influenced by stimulus relevance and expectations. This study provides evidence supporting aspects of predictive coding in the sensory cortex.

Protein language models-assisted optimization of a uracil-N-glycosylase variant enables programmable T-to-G and T-to-C base editing.

Current base editors (BEs) use DNA deaminases, including cytidine deaminase in cytidine BE (CBE) or adenine deaminase in adenine BE (ABE), to facilitate transition nucleotide substitutions. Combining CBE or ABE with glycosylase enzymes can induce limited transversion mutations. Nonetheless, a critical demand remains for BEs capable of generating alternative mutation types, such as T>G corrections. In this study, we leveraged pre-trained protein language models to optimize a uracil-N-glycosylase (UNG) variant with altered specificity for thymines (eTDG). Notably, after two rounds of testing fewer than 50 top-ranking variants, more than 50% exhibited over 1.5-fold enhancement in enzymatic activities. When eTDG was fused with nCas9, it induced programmable T-to-S (G/C) substitutions and corrected db/db diabetic mutation in mice (up to 55%). Our findings not only establish orthogonal strategies for developing novel BEs but also demonstrate the capacities of protein language models for optimizing enzymes without extensive task-specific training data.

HIV Disclosure Among Sexually Infected People Living with HIV and AIDS in China: Prevalence, Influencing Factors, and Negative Outcomes.

HIV disclosure is crucial for HIV prevention and control, but may also lead to discrimination, insult, and even violence against people living with HIV and AIDS (PLWHAs). In this study, we examined HIV disclosure, its influencing factors, and its association with intimate partner violence (IPV) among 1153 PLWHAs through the sexual route in Jinan, Shandong Province, China. Our results showed that 76.4% (881/1153) PLWHAs had disclosed someone about their HIV infection, the HIV disclosure rates among family members, friends, spouses, and current fixed partners of PLWHAs were 43.5% (501/1153), 47.9% (552/1153), 56.8% (129/227), and 43.2% (336/777), respectively. HIV disclosure was affected by socio-demographics, disease characteristics, and psycho-social factors and varied among family members, close friends, spouses, and current fixed sexual partners. Age ≤ 33 years (aOR 1.79, 95% CI 1.27-2.53), heterosexual infection route (aOR 1.52, 95% CI 1.06-2.17), HIV diagnosis time > 36 months (aOR 1.84, 95% CI 1.30-2.59), with other chronic diseases (aOR 1.87, 95% CI 1.34-2.61), lower self-stigma (aOR 4.03-4.36, 95% CI 1.98-8.74), higher social support (aOR 1.71-1.73, 95% CI 1.03-2.83), no depression (aOR 1.54, 95% CI 1.12-2.11), and no suicidal ideation (aOR 1.79, 95% CI 1.28-2.50) were all independently associated with increased likelihood of HIV disclosure. HIV disclosure was associated with an increased risk of IPV among current fixed sexual partners (aOR 1.87, 95% CI 1.38-2.54) and spouses (aOR 2.54, 95% CI 1.41-4.56). Our findings suggest that the HIV disclosure rate of PLWHAs is still low and is affected by multiple factors. There is an urgent need to design targeted and comprehensive interventions to improve HIV disclosure. IPV prevention should also be incorporated into the intervention system of HIV disclosure to ensure adequate and continuous support for PLWHAs.

Multi-level metabolic engineering of Pseudomonas mutabilis ATCC31014 for efficient production of biotin.

Biotin (Vitamin H or B7) is one of the most important cofactors involved in central metabolism of pro- and eukaryotic cells. Currently, chemical synthesis is the only route for commercial production. This study reports efficient microbial production of biotin in Pseudomonas mutabilis via multi-level metabolic engineering strategies: Level 1, overexpressing rate-limiting enzyme encoding genes involved in biotin synthesis (i.e. promoter and ribosome binding site engineering); Level 2, deregulating biotin biosynthesis (i.e. deletion of the negative regulator and the biotin importer genes); Level 3, enhancing the supply of co-factors (i.e. S-adenosyl-L-methionine and [Fe-S] cluster) for biotin biosynthesis; Level 4, increasing the availability of the precursor pimelate thioester (i.e. introduction of the BioW-BioI pathway from Bacillus subtilis). The combination of these interventions resulted in the establishment of a biotin overproducing strain, with the secretion of biotin increased for more than 460-fold. In combination with bioprocess engineering efforts, biotin was produced at a final titer of 87.17 mg/L in a shake flask and 271.88 mg/L in a fed-batch fermenter with glycerol as the carbon source. This is the highest biotin titer ever reported so far using rationally engineered microbial cell factories.