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The epiblast (EPI) is the origin of all somatic and germ cells in mammals, and of pluripotent stem cells in vitro . To explore the ontogeny of human and primate pluripotency, here we perform comprehensive single-cell RNA sequencing for pre- and post-implantation EPI development in cynomolgus monkeys ( Macaca fascicularis ). We show that after specification in the blastocysts, EPI from cynomolgus monkeys (cyEPI) undergoes major transcriptome changes on implantation. Thereafter, while generating gastrulating cells, cyEPI stably maintains its transcriptome over a week, retains a unique set of pluripotency genes and acquires properties for ‘neuron differentiation’. Human and monkey pluripotent stem cells show the highest similarity to post-implantation late cyEPI, which, despite co-existing with gastrulating cells, bears characteristics of pre-gastrulating mouse EPI and epiblast-like cells in vitro . These findings not only reveal the divergence and coherence of EPI development, but also identify a developmental coordinate of the spectrum of pluripotency among key species, providing a basis for better regulation of human pluripotency in vitro . Using a single-cell sequencing analysis in monkey embryos, and comparing the genes expressed during early development in this species with those in mice and in human pluripotent stem cells, the authors define characteristics of pluripotency ontogeny across mammalian species. Species differences in developing pluripotent stem cells Using a single-cell-sequencing-based analysis in monkey embryos, and comparing the genes expressed during early development in this species and what is known from mouse and human studies, Mitinori Saitou and colleagues define characteristics of pluripotency ontogeny across mammalian species. They show that, surprisingly, monkey cells undergoing neuronal differentiation continue to express genes associated with pluripotency during gastrulation. The analysis also provides insights into the comparative properties of developmental-stage pluripotent stem cells in key species that will help to establish a basis for better regulation of human pluripotency in vitro .

Over the millennia, indigenous small tanks (small reservoirs or ponds) have served to store rainwater and surface runoff to irrigate drylands. However, despite their significance, small tanks have been gradually abandoned in drylands over the past decades to expand cultivable areas under modern agricultural interventions, such as dam reservoirs and canal systems. Sole reliance on modern water interventions has intensified freshwater stress and rendered dryland agriculture vulnerable to droughts. Herein, we present a sociohydrological model incorporating the concept of human salience (i.e., attention accorded by farmers based on actual and perceived reservoir water availability and rainfall) and access to small tanks to simulate farmer decisions on cultivation area. By applying the model to a centrally managed modern irrigation system and a quasi-decentralized indigenous irrigation system in the Mahaweli H irrigation scheme of the Sri Lankan dry zone for the 2010–2020 period, we calibrated farmer perception levels to show that indigenous system farmers perceive a significantly low rainfall threshold indicating greater adaptability to dry conditions. Sensitivity of perception levels to cultivation area demonstrate that modern system farmers have an 18% higher dependency on reservoir water availability compared to indigenous farmers when deciding cultivation area. This stark dependency on reservoir water availability of modern system farmers is rooted in lack of accessibility to small tanks, a feature that enhance drought resilience of farmers in the indigenous system. While providing quantifiable insights, this comparative assessment underscores the importance of critically evaluating the efficacy of decentralized indigenous small tanks in current water resource investments.

The wave of modernization and globalization in the last century has rapidly involved a technological paradigm shift from indigenous irrigation water systems to modern systems in arid regions. Despite interest in the drought resilience of indigenous water systems, the impact of this paradigm shift on drought resilience remains poorly understood because previous studies have focused on fixed irrigation water systems. To fill this gap, we investigated the drought resilience of an indigenous and modern irrigation water system that coexists in the drought-prone Mahaweli H region of the Sri Lankan dry zone. To explain drought resilience, we quantified the historical irrigation system performance (1985–2021) of both water systems using the water duty indicator (i.e., the volume of water required to cultivate a unit land area). The statistical Pettitt test was used to detect significant change points in the time series of water duty, and we divided the time line into few periods based on the change points. Furthermore, a quantitative trend analysis of several socio-hydrological variables and a qualitative analysis of their socio-hydrological backgrounds with triggers of water duty were conducted to explain drought resilience path dependency in modern and indigenous water systems. The results indicated a higher drought resilience is embedded in the indigenous system as the mean water duty increment in drought years compared to non-drought years is 16.4% for the indigenous system and 58.3% for the modern system. In addition, drought resilience pathways that elucidated by water duty change points also demonstrated that indigenous water system features a higher drought resilience compared to the modern water system. The findings of this comparative study can contribute to the design of drought resilience improvement strategies in arid region irrigation water systems in a more comprehensive manner.

Arsenic contamination not only complicates mineral processing but also poses environmental and health risks. To address these challenges, this research investigates the feasibility of utilizing Hyperspectral imaging combined with machine learning techniques for the identification of arsenic-containing minerals in copper ore samples, with a focus on practical application in sorting and processing operations. Through experimentation with various copper sulfide ores, Neighborhood Component Analysis (NCA) was employed to select essential wavelength bands from Hyperspectral data, subsequently used as inputs for machine learning algorithms to identify arsenic concentrations. Results demonstrate that by selecting a subset of informative bands using NCA, accurate mineral identification can be achieved with a significantly reduced the size of dataset, enabling efficient processing and analysis. Comparison with other wavelength selection methods highlights the superiority of NCA in optimizing classification accuracy. Specifically, the identification accuracy showed 91.9% or more when utilizing 8 or more bands selected by NCA and was comparable to hyperspectral data analysis with 204 bands. The findings suggest potential for cost-effective implementation of multispectral cameras in mineral processing operations. Future research directions include refining machine learning algorithms, exploring broader applications across diverse ore types, and integrating hyperspectral imaging with emerging sensor technologies for enhanced mineral processing capabilities.

The octanol–water partition coefficient (logPow) is an important index for measuring solubility, membrane permeability, and bioavailability in the drug discovery field. In this paper, the logPow values of 58 compounds were predicted by alchemical free energy calculation using molecular dynamics simulation. In free energy calculations, the atomic charges of the compounds are always fixed. However, they must be recalculated for each solvent. Therefore, three different sets of atomic charges were tested using quantum chemical calculations, taking into account vacuum, octanol, and water environments. The calculated atomic charges in the different environments do not necessarily influence the correlation between calculated and experimentally measured ∆Gwater values. The largest correlation coefficient values of the solvation free energy in water and octanol were 0.93 and 0.90, respectively. On the other hand, the correlation coefficient of logPow values calculated from free energies, the largest of which was 0.92, was sensitive to the combination of the solvation free energies calculated from the calculated atomic charges. These results reveal that the solvent assumed in the atomic charge calculation is an important factor determining the accuracy of predicted logPow values.

IntroductionThe relationship between postoperative tibiofemoral ligament balance and patient satisfaction in total knee arthroplasty (TKA) has been explored previously. However, the optimal intraoperative medial–lateral ligament balance during knee flexion in terms of postoperative patient satisfaction remains unknown. We evaluated the effect of intraoperative flexion instability on patient satisfaction after TKA.Materials and methodsThis study consisted of 46 knees with varus osteoarthritis undergoing TKA. Medial–lateral component gaps at 0° knee extension and 90° flexion were measured intraoperatively using a knee balancer. Differences in postoperative patient outcomes at 3 weeks and 1 year were compared between medially tight knees in 90° flexion with a medial component gap of < 4 mm and medially loose knees in 90° flexion with a gap of ≥ 4 mm. Outcomes were measured using the 2011 Knee Society Scoring System (2011 KS).ResultsThe median total 2011 KS score at 1 year postoperatively in the medially loose knees [median 97; interquartile range (IQR) 75–117] was significantly lower than that in the medially tight knees (median 128; IQR 104–139, P < 0.01), while preoperative and 3-week postoperative scores were similar. In addition, medial flexion gaps were not significantly associated with total 2011 KS scores before surgery or at 3 weeks postoperatively. However, at 1 year after surgery, medial component flexion gaps were negatively associated with the total 2011 KS score (R = − 0.42; P < 0.01) and the 2011 KS satisfaction subscale score (R = − 0.36; P = 0.01).ConclusionsExcessive intraoperative medial joint laxity of ≥ 4 mm at 90° flexion progressively decreased patient satisfaction for 1 year. Since intraoperative medial laxity in flexion is likely to interfere with functional recovery after TKA, medial stabilization during TKA is important throughout knee flexion.Level of evidenceTherapeutic study, Level III.

This study explores the potential of accelerometer-based gait analysis as a non-invasive approach for predicting cognitive impairment in older adults. A total of 75 participants (61.3% female; mean age: 78.9 years), including cognitively normal individuals and patients with dementia, were enrolled. Walking data were collected using a six-axis waist-worn accelerometer during self-paced locomotion. Allan variance (AVAR), a robust statistical measure of frequency stability, was applied to characterize gait dynamics. AVAR-derived features, combined with participant age, were used as inputs to machine learning models, logistic regression and Light Gradient Boosting Machine (LightGBM) for classifying cognitive status based on Mini-Mental State Examination (MMSE) scores. LightGBM achieved superior performance (AUC = 0.92) compared to logistic regression (AUC = 0.85). Although mild cognitive impairment (MCI) cases were grouped with cognitively normal participants, gait-based classification revealed that MCI individuals exhibited patterns more similar to those with cognitive impairment. These results suggest that AVAR-based gait features are promising for early detection of cognitive decline in older adults.

Purpose One of the causes of aseptic loosening is marked tibial bone resorption (TR) at the tibial bone–component interface after total knee arthroplasty (TKA). It was hypothesized that insufficient coverage of the tibial component and improper cementing technique would cause increased TR after cemented TKA. Methods One hundred thirty-four primary TKAs in 107 patients with varus osteoarthritis were included in this study. The relationships between the TRs at 2 years after TKA and the tibial component underhang (TUH), the thickness of the cement mantle around the keel, and clinical parameters were evaluated. Results The widths of TRs on anteroposterior radiographs were significantly larger on the medial side than on the lateral side ( p  = 0.001), whereas the difference between the anterior and posterior sides on lateral radiographs was relatively small. Multiple regression analyses showed that medial TR was positively related to medial TUH ( p  = 0.006), and lateral TR was positively related to a thicker distal cement mantle ( p  = 0.027). On the lateral view, stepwise selection indicated that postoperative knee flexion angle was the most significant risk factor ( p  = 0.005) for anterior TR, and posterior TUH was the strongest predictor ( p  = 0.001) of posterior TR. Conclusions To avert postoperative progressive TR, surgeons should perfectly fit a suitably sized tibial component to the medial edge of the tibia. Also, care should be taken to avoid an excessive cement mantle at the distal portion of the keel during TKA. Level of evidence IV.

Background Polygenic risk score (PRS) analysis is used to predict disease risk. Although PRS has been shown to have great potential in improving clinical care, PRS accuracy assessment has been mainly focused on European ancestry. This study aimed to develop an accurate genetic risk score for knee osteoarthritis (OA) using a multi-population PRS and leveraging a multi-trait PRS in the Japanese population. Methods We calculated PRS using PRS-CS-auto, derived from genome-wide association study (GWAS) summary statistics for knee OA in the Japanese population (same ancestry) and multi-population. We further identified risk factor traits for which PRS could predict knee OA and subsequently developed an integrated PRS based on multi-trait analysis of GWAS (MTAG), including genetically correlated risk traits. PRS performance was evaluated in participants of the Nagahama cohort study who underwent radiographic evaluation of the knees ( n  = 3,279). PRSs were incorporated into knee OA integrated risk models along with clinical risk factors. Results A total of 2,852 genotyped individuals were included in the PRS analysis. The PRS based on Japanese knee OA GWAS was not associated with knee OA ( p  = 0.228). In contrast, PRS based on multi-population knee OA GWAS showed a significant association with knee OA ( p  = 6.7 × 10 −5 , odds ratio (OR) per standard deviation = 1.19), whereas PRS based on MTAG of multi-population knee OA, along with risk factor traits such as body mass index GWAS, displayed an even stronger association with knee OA ( p  = 5.4 × 10 −7 , OR = 1.24). Incorporating this PRS into traditional risk factors improved the predictive ability of knee OA (area under the curve, 74.4% to 74.7%; p  = 0.029). Conclusions This study showed that multi-trait PRS based on MTAG, combined with traditional risk factors, and using large sample size multi-population GWAS, significantly improved predictive accuracy for knee OA in the Japanese population, even when the sample size of GWAS of the same ancestry was small. To the best of our knowledge, this is the first study to show a statistically significant association between the PRS and knee OA in a non-European population. Trial registration No. C278.

Background and Objective For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC. Methods Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy. Results In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan–Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%. Conclusions These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC. Clinical Trial Registration ClinicalTrials.gov identifier NCT02358395, registered on 9 February 2015.