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Cholesterol in the body comes from what is absorbed from diet and from what is synthesized in the body, mainly by the liver. In the 1960s it was shown that, in humans, cholesterol produced in the liver exceeds what is absorbed from the diet. 3-Hydroxy-3- methylglutaryl (HMG)-CoA reductase, an enzyme that catalyzes the conversion of HMGCoA into mevalonate, proved to be the rate-controlling enzyme in cholesterol synthesis.

CRISPR/Cas9 systems are nowadays applied extensively to effect genome editing in various organisms including plants. CRISPR from Prevotella and Francisella 1 (Cpf1) is a newly characterized RNA-guided endonuclease that has two distinct features as compared to Cas9. First, Cpf1 utilizes a thymidine-rich protospacer adjacent motif (PAM) while Cas9 prefers a guanidine-rich PAM. Cpf1 could be used as a sequence-specific nuclease to target AT-rich regions of a genome that Cas9 had difficulty accessing. Second, Cpf1 generates DNA ends with a 5′ overhang, whereas Cas9 creates blunt DNA ends after cleavage. “Sticky” DNA ends should increase the efficiency of insertion of a desired DNA fragment into the Cpf1-cleaved site using complementary DNA ends. Therefore, Cpf1 could be a potent tool for precise genome engineering. To evaluate whether Cpf1 can be applied to plant genome editing, we selected Cpf1 from Francisella novicida (FnCpf1), which recognizes a shorter PAM (TTN) within known Cpf1 proteins, and applied it to targeted mutagenesis in tobacco and rice. Our results show that targeted mutagenesis had occurred in transgenic plants expressing FnCpf1 with crRNA. Deletions of the targeted region were the most frequently observed mutations. Our results demonstrate that FnCpf1 can be applied successfully to genome engineering in plants.

Background A recurrent feature of infectious diseases is the observation that different individuals show different levels of secondary transmission. This inter-individual variation in transmission potential is often quantified by the dispersion parameter k. Low values of k indicate a high degree of variability and a greater probability of superspreading events. Understanding k for COVID-19 across contexts can assist policy makers prepare for future pandemics. Methods A literature search following a systematic approach was carried out in PubMed, Embase, Web of Science, Cochrane Library, medRxiv, bioRxiv and arXiv to identify publications containing epidemiological findings on superspreading in COVID-19. Study characteristics, epidemiological data, including estimates for k and R0, and public health recommendations were extracted from relevant records. Results The literature search yielded 28 peer-reviewed studies. The mean k estimates ranged from 0.04 to 2.97. Among the 28 studies, 93% reported mean k estimates lower than one, which is considered as marked heterogeneity in inter-individual transmission potential. Recommended control measures were specifically aimed at preventing superspreading events. The combination of forward and backward contact tracing, timely confirmation of cases, rapid case isolation, vaccination and preventive measures were suggested as important components to suppress superspreading. Conclusions Superspreading events were a major feature in the pandemic of SARS-CoV-2. On the one hand, this made outbreaks potentially more explosive but on the other hand also more responsive to public health interventions. Going forward, understanding k is critical for tailoring public health measures to high-risk groups and settings where superspreading events occur.

The majority of its outbound travel volume is for south, southeast, and east Asian countries with relatively large population sizes (figure; data sources detailed in appendix p 1). Some of these countries have reported new cases in 2023 (both with and without a travel history), with at least one of these cases as of March, 2023, having probably been infected in Japan (appendix p 6). Because of the scarcity of mpox vaccination campaigns in Asia (including Japan), these new infections raise a concern that the global mpox outbreak might be entering another phase—a resurgence formed by the spread in Asia. AE is supported by the Japan Society for the Promotion of Science (JSPS) Overseas Research Fellowships, JSPS Grants-in-Aid KAKENHI (22K17329), foundation for the Fusion Of Science and Technology, and Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology (JPMJPR22R3).

The CRISPR/Cas9 system is an efficient and convenient tool for genome editing in plants. Cas9 nuclease derived from Streptococcus pyogenes (Sp ) is commonly used in this system. Recently, Staphylococcus aureus Cas9 (SaCas9)-mediated genome editing was reported in human cells and Arabidopsis . Because SaCas9 (1053 a.a.) is smaller than SpCas9 (1368 a.a.), SaCas9 could have substantial advantages for delivering and expressing Cas9 protein, especially using virus vectors. Since the protospacer adjacent motif (PAM) sequence of SaCas9 (5′-NNGRRT-3′) differs from that of SpCas9 (5′-NGG-3′), the use of this alternative Cas9 nuclease could expand the selectivity at potential cleavage target sites of the CRISPR/Cas9 system. Here we show that SaCas9 can mutagenize target sequences in tobacco and rice with efficiencies similar to those of SpCas9. We also analyzed the base preference for ‘T’ at the 6th position of the SaCas9 PAM. Targeted mutagenesis efficiencies in target sequences with non-canonical PAMs (5′-NNGRRV-3′) were much lower than those with a canonical PAM (5′-NNGRRT-3′). The length of target sequence recognized by SaCas9 is one or two nucleotides longer than that recognized by SpCas9. Taken together, our results demonstrate that SaCas9 has higher sequence recognition capacity than SpCas9 and is useful for reducing off-target mutations in crop.

In a paper recently published in Nature Medicine, Fukumoto et al. tried to assess the government-led school closure policy during the early phase of the COVID-19 pandemic in Japan. They compared the reported incidence rates between municipalities that had and had not implemented school closure in selected periods from March-May 2020, where they matched for various potential confounders, and claimed that there was no causal effect on the incidence rates of COVID-19. However, the effective sample size (ESS) of their dataset had been substantially reduced in the process of matching due to imbalanced covariates between the treatment (i.e. with closure) and control (without closure) municipalities, which led to the wide uncertainty in the estimates. Despite the study title starting with \"No causal effect of school closures\", their results are insufficient to exclude the possibility of a strong mitigating effect of school closure on incidence of COVID-19. In this replication/reanalysis study, we showed that the confidence intervals of the effect estimates from Fukumoto et al. included a 100% relative reduction in COVID-19 incidence. Simulations of a hypothetical 50% or 80% mitigating effect hardly yielded statistical significance with the same study design and sample size. We also showed that matching of variables that had large influence on propensity scores (e.g. prefecture dummy variables) may have been incomplete.

The distribution of the generation time (the interval between individuals becoming infected and transmitting the virus) characterises changes in the transmission risk during SARS-CoV-2 infections. Inferring the generation time distribution is essential to plan and assess public health measures. We previously developed a mechanistic approach for estimating the generation time, which provided an improved fit to data from the early months of the COVID-19 pandemic (December 2019-March 2020) compared to existing models (Hart et al., 2021). However, few estimates of the generation time exist based on data from later in the pandemic. Here, using data from a household study conducted from March to November 2020 in the UK, we provide updated estimates of the generation time. We considered both a commonly used approach in which the transmission risk is assumed to be independent of when symptoms develop, and our mechanistic model in which transmission and symptoms are linked explicitly. Assuming independent transmission and symptoms, we estimated a mean generation time (4.2 days, 95% credible interval 3.3–5.3 days) similar to previous estimates from other countries, but with a higher standard deviation (4.9 days, 3.0–8.3 days). Using our mechanistic approach, we estimated a longer mean generation time (5.9 days, 5.2–7.0 days) and a similar standard deviation (4.8 days, 4.0–6.3 days). As well as estimating the generation time using data from the entire study period, we also considered whether the generation time varied temporally. Both models suggest a shorter mean generation time in September-November 2020 compared to earlier months. Since the SARS-CoV-2 generation time appears to be changing, further data collection and analysis is necessary to continue to monitor ongoing transmission and inform future public health policy decisions.

Seeds respond to multiple different environmental stimuli that regulate germination. Nitrate stimulates germination in many plants but how it does so remains unclear. Here we show that the Arabidopsis NIN-like protein 8 (NLP8) is essential for nitrate-promoted seed germination. Seed germination in nlp8 loss-of-function mutants does not respond to nitrate. NLP8 functions even in a nitrate reductase-deficient mutant background, and the requirement for NLP8 is conserved among Arabidopsis accessions. NLP8 reduces abscisic acid levels in a nitrate-dependent manner and directly binds to the promoter of CYP707A2, encoding an abscisic acid catabolic enzyme. Genetic analysis shows that NLP8-mediated promotion of seed germination by nitrate requires CYP707A2. Finally, we show that NLP8 localizes to nuclei and unlike NLP7, does not appear to be activated by nitrate-dependent nuclear retention of NLP7, suggesting that seeds have a unique mechanism for nitrate signalling.

The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival. The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.

Background Hospital- and community-onset sepsis are significant sepsis subgroups. Japanese data comparing these subgroups are limited. This study aimed to describe the epidemiology of hospital- and community-onset sepsis in critical care units in Japan. Methods We performed a retrospective cohort study using the Japanese Diagnosis and Procedure Combination database. Adult patients admitted to critical care units with sepsis from April 2010 to March 2020 were included. Sepsis cases were identified based on ICD-10 codes for infectious diseases, procedure codes for blood culture tests, and medication codes for antimicrobials. Patients’ characteristics, in-hospital mortality, and resource utilization were assessed. The in-hospital mortality between groups was compared using the Poisson regression generalized linear mixed-effect model. Results Of 516,124 patients, 52,183 (10.1%) had hospital-onset sepsis and 463,940 (89.9%) had community-onset sepsis. Hospital-onset sepsis was characterized by younger age, infrequent emergency hospitalization, frequent surgery under general anesthesia, and frequent organ support upon critical care unit admission compared to community-onset sepsis. In-hospital mortality was higher for hospital-onset than for community-onset sepsis (35.5% versus 19.2%; unadjusted mean difference, 16.3% [95% confidence interval (CI) 15.9–16.7]; adjusted mean difference, 15.6% [95% CI 14.9–16.2]). Mean hospital length of stay was longer for hospital-onset than for community-onset sepsis (47 days versus 30 days; unadjusted mean difference, 17 days [95% CI 16–17]; adjusted mean difference, 13 days [95% CI 12–14]). Conclusion Patients with hospital-onset sepsis admitted to critical care units in Japan had a poorer prognosis and more resource utilization including organ support rate, number of days with critical care unit surcharge codes, and hospital length of stay than those with community-onset sepsis.