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Sequence-specific nucleases are commonly used to modify the nuclear genome of plants. However, targeted modification of the mitochondrial genome of land plants has not yet been achieved. In plants, a type of male sterility called cytoplasmic male sterility (CMS) has been attributed to certain mitochondrial genes, but none of these genes has been validated by direct mitochondrial gene-targeted modification. Here, we knocked out CMS-associated genes ( orf79 and orf125 ) of CMS varieties of rice and rapeseed, respectively, using transcription activator-like effector nucleases (TALENs) with mitochondria localization signals (mitoTALENs). We demonstrate that knocking out these genes cures male sterility, strongly suggesting that these genes are causes of CMS. Sequencing revealed that double-strand breaks induced by mitoTALENs were repaired by homologous recombination, and that during this process, the target genes and surrounding sequences were deleted. Our results show that mitoTALENs can be used to stably and heritably modify the mitochondrial genome in plants. Knockout of cytoplasmic male-sterility-associated genes using TALENs with mitochondria localization signals rescues male sterility in rice and rapeseed, validating the role of these genes, and provides a method for plant mitochondrial genome editing.

Short-pulsed lasers can treat dermal pigmented lesions through selective photothermolysis. The irradiated light experiences multiple scattering by the skin and is absorbed by abnormal melanosomes as well as by normal blood vessels above the target. Because the fluence is extremely high, the absorbed light can cause thermal damage to the adjacent tissue components, leading to complications. To minimize radiant exposure and reduce the risk of burns, a model of the melanosome-disruption threshold fluence (MDTF) has been developed that accounts for the light-propagation efficiency in the skin. However, the light-propagation efficiency is attenuated because of multiple scattering, which limits the extent to which the radiant exposure required for treatment can be reduced. Here, this study demonstrates the principle of melanosome disruption with localized thermal damage through a turbid medium by ultralow radiant exposure of a short-pulsed laser. The MDTF model was combined with a wavefront-shaping technique to design an irradiation condition that can increase the light-propagation efficiency to the target. Under this irradiation condition, melanosomes were disrupted at a radiant exposure 25 times lower than the minimal value used in conventional laser treatments. Furthermore, almost no thermal damage to the skin was confirmed through a numerical simulation. These experimental and numerical results show the potential for noninvasive melanosome disruption and may lead to the improvement of the safety of short-pulsed laser treatment.

NRC publication: Yes

Laser ablation is a minimally invasive therapeutic technique to denature tumors through coagulation and/or vaporization. Computational simulations of laser ablation can evaluate treatment outcomes quantitatively and provide numerical indices to determine treatment conditions, thus accelerating the technique’s clinical application. These simulations involve calculations of light transport, thermal diffusion, and the extent of thermal damage. The optical properties of tissue, which govern light transport through the tissue, vary during heating, and this affects the treatment outcomes. Nevertheless, the optical properties in conventional simulations of coagulation and vaporization remain constant. Here, we propose a laser ablation simulation based on Monte Carlo light transport with a dynamic optical properties (DOP) model. The proposed simulation is validated by performing optical properties measurements and laser irradiation experiments on porcine liver tissue. The DOP model showed the replicability of the changes in tissue optical properties during heating. Furthermore, the proposed simulation estimated coagulation areas that were comparable to experimental results at low-power irradiation settings and provided more than 2.5 times higher accuracy when calculating coagulation and vaporization areas than simulations using static optical properties at high-power irradiation settings. Our results demonstrate the proposed simulation’s applicability to coagulation and vaporization region calculations in tissue for retrospectively evaluating the treatment effects of laser ablation.

Interprofessional education (IPE) is crucial in dentistry, medicine, and nursing. However, scant mixed methods studies have compared the IPE outcomes across these disciplines to develop evidence-based IPE. This study explored the differences in the readiness of dental, medical, and nursing students for interprofessional learning before and after IPE workshops and elucidated reasons for this disparity. Data were obtained from dental, medical, and nursing students who participated in IPE workshops conducted at Tokyo Medical and Dental University in Japan in 2019 and 2020. The participants filled the validated Japanese version of the Readiness for Interprofessional Learning Scale (RIPLS) before and after attending the workshops (n = 378). Paired t-tests were performed to assess differences between the pre- and post- workshop RIPLS scores. Welch's t-tests were deployed to evaluate interdisciplinary differences in their scores. Qualitative analyses were conducted using an explanatory sequential design with focus group discussions (FGDs) held with 17 dental students to explain the quantitative results. Total RIPLS scores increased significantly for every discipline after the workshops (p < 0.001). Dental students scored significantly lower pre- and post- workshop aggregates than medical and nursing students, respectively (p < 0.001). The FGDs yielded three principal themes in the explanations tendered by dental students on their lower scores: 1) dental students rarely felt the need for interprofessional collaborations, 2) dentists often worked without the need for interprofessional collaborations, and 3) dental students believed their contribution to the workshop was insufficient. The results revealed divergences in the readiness of dental, medical, and nursing students for interprofessional learning, and the study illuminated possible reasons for these disparities. These outcomes will help develop evidence-based IPE by indicating approaches to place a higher value on interprofessional collaborations in educational environments, ameliorate the awareness of educators, and enhance the workshop facilitation style.

Data assimilation systems are used increasingly to constrain the budgets of reactive and long-lived gases measured in the atmosphere. Each trace gas has its own lifetime, dominant sources and sinks, and observational network (from flask sampling and in situ measurements to space-based remote sensing) and therefore comes with its own optimal configuration of the data assimilation. The CarbonTracker Europe data assimilation system for CO2 estimates global carbon sources and sinks, and updates are released annually and used in carbon cycle studies. CarbonTracker Europe simulations are performed using the new modular implementation of the data assimilation system: the CarbonTracker Data Assimilation Shell (CTDAS). Here, we present and document this redesign of the data assimilation code that forms the heart of CarbonTracker, specifically meant to enable easy extension and modification of the data assimilation system. This paper also presents the setup of the latest version of CarbonTracker Europe (CTE2016), including the use of the gridded state vector, and shows the resulting carbon flux estimates. We present the distribution of the carbon sinks over the hemispheres and between the land biosphere and the oceans. We show that with equal fossil fuel emissions, 2015 has a higher atmospheric CO2 growth rate compared to 2014, due to reduced net land carbon uptake in later year. The European carbon sink is especially present in the forests, and the average net uptake over 2001–2015 was 0. 17 ± 0. 11 PgC yr−1 with reductions to zero during drought years. Finally, we also demonstrate the versatility of CTDAS by presenting an overview of the wide range of applications for which it has been used so far.

The microbiota of whole crop corn silage and feces of silage-fed dairy cows were examined. A total of 18 dairy cow feces were collected from six farms in Japan and China, and high-throughput Illumina sequencing of the V4 hypervariable region of 16S rRNA genes was performed. Lactobacillaceae were dominant in all silages, followed by Acetobacteraceae , Bacillaceae , and Enterobacteriaceae . In feces, the predominant families were Ruminococcaceae , Bacteroidaceae , Clostridiaceae , Lachnospiraceae , Rikenellaceae , and Paraprevotellaceae . Therefore, Lactobacillaceae of corn silage appeared to be eliminated in the gastrointestinal tract. Although fecal microbiota composition was similar in most samples, relative abundances of several families, such as Ruminococcaceae , Christensenellaceae , Turicibacteraceae , and Succinivibrionaceae , varied between farms and countries. In addition to the geographical location, differences in feeding management between total mixed ration feeding and separate feeding appeared to be involved in the variations. Moreover, a cow-to-cow variation for concentrate-associated families was demonstrated at the same farm; two cows showed high abundance of Succinivibrionaceae and Prevotellaceae , whereas another had a high abundance of Porphyromonadaceae . There was a negative correlation between forage-associated Ruminococcaceae and concentrate-associated Succinivibrionaceae and Prevotellaceae in 18 feces samples. Succinivibrionaceae , Prevotellaceae , p-2534-18B5 , and Spirochaetaceae were regarded as highly variable taxa in this study. These findings help to improve our understanding of variation and similarity of the fecal microbiota of dairy cows with regard to individuals, farms, and countries. Microbiota of naturally fermented corn silage had no influence on the fecal microbiota of dairy cows.

Background Hyperuricemia is a recognized risk factor for chronic kidney disease (CKD). Dotinurad, a novel selective urate reabsorption inhibitor, effectively lowers uric acid (UA) levels. However, longitudinal patterns of UA after treatment initiation and changes in estimated glomerular filtration rate (eGFR) slope across the pre-initiation and post-initiation periods remain insufficiently characterized. Methods We retrospectively identified patients with hyperuricemia who initiated dotinurad therapy. Eligible patients required a baseline eGFR and at least two eGFR measurements during both the pre-initiation period (3, 6, or 12 months before initiation) and the post-initiation period (3, 6, or 12 months after initiation). UA levels were assessed at baseline and at 3, 6, and 12 months. Longitudinal changes in UA and eGFR slopes were evaluated using linear mixed-effects models. Results Among 135 screened patients, 68 met the inclusion criteria. The mean age was 59 years, and 73.5% were male. The median baseline eGFR was 50.4 mL/min/1.73 m². UA levels were lower at 3, 6, and 12 months compared with baseline (all P  < 0.001). The annual eGFR slope was − 5.7 mL/min/1.73 m²/year (95% confidence interval [CI] − 8.3 to − 3.2) before initiation and 0.6 mL/min/1.73 m²/year (95% CI − 0.6 to 1.8) after initiation. The difference in slopes was statistically significant ( P for interaction = 0.003). Similar patterns were observed in multivariable models adjusted for baseline eGFR, age, sex, and sodium–glucose cotransporter 2 inhibitor use. Conclusion In this retrospective cohort, dotinurad use was associated with lower UA levels and a less negative eGFR slope over time. These findings describe real-world patterns of UA levels after treatment initiation and changes in eGFR slope before and after treatment initiation, and they support the need for prospective studies evaluating kidney outcomes.

We present a case of a 51‐year‐old woman with atrial septal defect (ASD) masked by pulmonary arterial hypertension (PAH). Three months after PAH treatment with a combination of endothelin receptor antagonist and phosphodiesterase five inhibitor, the transthoracic echocardiography revealed left‐to‐right shunting through a secundum ASD. The pulmonary vascular resistance decreased from 7.4 to 2.6 Wood units. Subsequent transcatheter closure of ASD using Occlutech Figulla Flex II device was successfully performed as a treat‐and‐repair strategy. Five months later, hemodynamics had normalized. Due to reduced shunt flow caused by PAH, ASD may not be detectable before treatment, so care must be taken not to overlook PAH associated with intracardiac defects. Key Clinical Message In patients with pulmonary arterial hypertension, latent intracardiac shunts can emerge as pulmonary vascular resistance decreases. If a shunt cannot be excluded, transesophageal echocardiography or agitated saline contrast studies should be considered to identify underlying cardiac defects and guide appropriate treatment and long‐term clinical management.

Background: Endoscopic submucosal dissection (ESD) is a standard treatment for tumors of the gastrointestinal tract. We developed a self-completion method of ESD using Endosaber to eliminate the need for an additional device or human assistance during the procedure. The aim of this study was to evaluate the technical feasibility and outcomes of this method in an ex vivo porcine training model. Methods: This was a pilot study, and the procedures were performed by 4 experts. Mock lesions measuring 15 mm in diameter were prepared at the posterior wall in the middle or lower esophagus obtained from domestic pigs. Each operator performed ESD on the mock lesions in 3 models. The primary outcome was ESD completion rate using the self-completion method. The secondary outcomes were procedure time, en bloc resection rate, perforation rate, and number of injections during the procedure. Results: All 12 ESDs were completed using the self-completion method. The median procedure time (interquartile range) was 483.5 (399–619.3) s (median incision time: 240.4 [168.3–332.5] s; median dissection time: 222 [182.8–257] s). En bloc resection rate was 100%. No perforation was noted during any of the procedures. The median number of injections was 10.5 (9–14.3). The procedure time decreased significantly with increase in experience (p = 0.020). Conclusions: The self-completion ESD method using one Endosaber without any assistance achieved a 100% en bloc resection rate without any perforation. The need for an additional device or assistance was successfully eliminated. This method may prove to be a simple and cost-effective ESD procedure for lesions in humans.