Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice

新型コロナウイルスを中和するアルパカ抗体 --マウス実験で有効性を確認--. 京都大学プレスリリース. 2023-02-17.BACKGROUND: SARS-CoV-2 Omicron variants are highly resistant to vaccine-induced immunity and human monoclonal antibodies. METHODS: We previously reported that two nanobodies, P17 and P86, potently neutralize SARS-CoV-2 VOCs. In this study, we modified these nanobodies into trimers, called TP17 and TP86 and tested their neutralization activities against Omicron BA.1 and subvariant BA.2 using pseudovirus assays. Next, we used TP17 and TP86 nanobody cocktail to treat ACE2 transgenic mice infected with lethal dose of SARS-CoV-2 strains, original, Delta and Omicron BA.1. RESULTS: Here, we demonstrate that a novel nanobody TP86 potently neutralizes both BA.1 and BA.2 Omicron variants, and that the TP17 and TP86 nanobody cocktail broadly neutralizes in vitro all VOCs as well as original strain. Furthermore, intratracheal administration of this nanobody cocktail suppresses weight loss and prolongs survival of human ACE2 transgenic mice infected with SARS-CoV-2 strains, original, Delta and Omicron BA.1. CONCLUSIONS: Intratracheal trimerized nanobody cocktail administration suppresses weight loss and prolongs survival of SARS-CoV-2 infected mice

A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis

Adolescent idiopathic scoliosis (AIS) is the most common spinal deformity. We previously conducted a genome-wide association study (GWAS) and detected two loci associated with AIS. To identify additional loci, we extended our GWAS by increasing the number of cohorts (2,109 affected subjects and 11,140 control subjects in total) and conducting a whole-genome imputation. Through the extended GWAS and replication studies using independent Japanese and Chinese populations, we identified a susceptibility locus on chromosome 9p22.2 (p = 2.46 × 10−13; odds ratio = 1.21). The most significantly associated SNPs were in intron 3 of BNC2, which encodes a zinc finger transcription factor, basonuclin-2. Expression quantitative trait loci data suggested that the associated SNPs have the potential to regulate the BNC2 transcriptional activity and that the susceptibility alleles increase BNC2 expression. We identified a functional SNP, rs10738445 in BNC2, whose susceptibility allele showed both higher binding to a transcription factor, YY1 (yin and yang 1), and higher BNC2 enhancer activity than the non-susceptibility allele. BNC2 overexpression produced body curvature in developing zebrafish in a gene-dosage-dependent manner. Our results suggest that increased BNC2 expression is implicated in the etiology of AIS

Evidence of causality of low body mass index on risk of adolescent idiopathic scoliosis: a Mendelian randomization study

IntroductionAdolescent idiopathic scoliosis (AIS) is a disorder with a three-dimensional spinal deformity and is a common disease affecting 1-5% of adolescents. AIS is also known as a complex disease involved in environmental and genetic factors. A relation between AIS and body mass index (BMI) has been epidemiologically and genetically suggested. However, the causal relationship between AIS and BMI remains to be elucidated.Material and methodsMendelian randomization (MR) analysis was performed using summary statistics from genome-wide association studies (GWASs) of AIS (Japanese cohort, 5,327 cases, 73,884 controls; US cohort: 1,468 cases, 20,158 controls) and BMI (Biobank Japan: 173430 individual; meta-analysis of genetic investigation of anthropometric traits and UK Biobank: 806334 individuals; European Children cohort: 39620 individuals; Population Architecture using Genomics and Epidemiology: 49335 individuals). In MR analyses evaluating the effect of BMI on AIS, the association between BMI and AIS summary statistics was evaluated using the inverse-variance weighted (IVW) method, weighted median method, and Egger regression (MR-Egger) methods in Japanese.ResultsSignificant causality of genetically decreased BMI on risk of AIS was estimated: IVW method (Estimate (beta) [SE] = -0.56 [0.16], p = 1.8 × 10-3), weighted median method (beta = -0.56 [0.18], p = 8.5 × 10-3) and MR-Egger method (beta = -1.50 [0.43], p = 4.7 × 10-3), respectively. Consistent results were also observed when using the US AIS summary statistic in three MR methods; however, no significant causality was observed when evaluating the effect of AIS on BMI.ConclusionsOur Mendelian randomization analysis using large studies of AIS and GWAS for BMI summary statistics revealed that genetic variants contributing to low BMI have a causal effect on the onset of AIS. This result was consistent with those of epidemiological studies and would contribute to the early detection of AIS

A counter-based read circuit tolerant to process variation for low-voltage operating STT-MRAM

The capacity of embedded memory on LSIs has kept increasing. It is important to reduce the leakage power of embedded memory for low-power LSIs. In fact, the ITRS predicts that the leakage power in embedded memory will account for 40% of all power consumption by 2024 [1]. A spin transfer torque magneto-resistance random access memory (STT-MRAM) is promising for use as non-volatile memory to reduce the leakage power. It is useful because it can function at low voltages and has a lifetime of over 1016 write cycles [2]. In addition, the STT-MRAM technology has a smaller bit cell than an SRAM. Making the STT-MRAM is suitable for use in high-density products [3–7]. The STT-MRAM uses magnetic tunnel junction (MTJ). The MTJ has two states: a parallel state and an anti-parallel state. These states mean that the magnetization direction of the MTJ’s layers are the same or different. The directions pair determines the MTJ’s magneto- resistance value. The states of MTJ can be changed by the current flowing. The MTJ resistance becomes low in the parallel state and high in the anti-parallel state. The MTJ potentially operates at less than 0.4 V [8]. In other hands, it is difficult to design peripheral circuitry for an STT-MRAM array at such a low voltage. In this paper, we propose a counter-based read circuit that functions at 0.4 V, which is tolerant of process variation and temperature fluctuation

A counter-based read circuit tolerant to process variation for low-voltage operating STT-MRAM

The capacity of embedded memory on LSIs has kept increasing. It is important to reduce the leakage power of embedded memory for low-power LSIs. In fact, the ITRS predicts that the leakage power in embedded memory will account for 40% of all power consumption by 2024 [1]. A spin transfer torque magneto-resistance random access memory (STT-MRAM) is promising for use as non-volatile memory to reduce the leakage power. It is useful because it can function at low voltages and has a lifetime of over 1016 write cycles [2]. In addition, the STT-MRAM technology has a smaller bit cell than an SRAM. Making the STT-MRAM is suitable for use in high-density products [3–7]. The STT-MRAM uses magnetic tunnel junction (MTJ). The MTJ has two states: a parallel state and an anti-parallel state. These states mean that the magnetization direction of the MTJ’s layers are the same or different. The directions pair determines the MTJ’s magneto- resistance value. The states of MTJ can be changed by the current flowing. The MTJ resistance becomes low in the parallel state and high in the anti-parallel state. The MTJ potentially operates at less than 0.4 V [8]. In other hands, it is difficult to design peripheral circuitry for an STT-MRAM array at such a low voltage. In this paper, we propose a counter-based read circuit that functions at 0.4 V, which is tolerant of process variation and temperature fluctuation