First-in-human study of GFH018, a small molecule inhibitor of transforming growth factor-ß receptor I inhibitor, in patients with advanced solid tumors.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a cytokine with multiple functions, including cell growth regulation, extracellular matrix production, angiogenesis homeostasis adjustment and et al. TGF-ß pathway activation promotes tumor metastasis/progression and mediates epithelial-mesenchymal transmission suppressing immunosurveillance in advanced tumors. GFH018, a small molecule inhibitor blocking TGF-ß signal transduction, inhibits the progression and/or metastasis of advanced cancers. This first-in-human study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of GFH018 monotherapy in patients with advanced solid tumors. METHODS: This phase I, open-label, multicenter study used a modified 3+3 dose escalation and expansion design. Adult patients with advanced solid tumors failing the standard of care were enrolled. Starting at 5 mg, eight dose levels up to 85 mg were evaluated. Patients received GFH018 BID (14d-on/14d-off) starting on the 4th day after a single dose on cycle 1, day 1. Subsequent cycles were defined as 28 days. The study also explored the safety of 85 mg BID 7d-on/7d-off. Adverse events were graded using NCI criteria for adverse events (NCI-CTCAE v5.0). PK was analyzed using a noncompartmental method. Efficacy was evaluated using RECIST 1.1. Blood samples were collected for biomarker analysis. RESULTS: Fifty patients were enrolled and received at least one dose of GFH018. No dose-limiting toxicity occurred, and the maximum tolerated dose was not reached. Forty-three patients (86.0%) had at least one treatment-related adverse event (TRAE), and three patients (6.0%) had ≥ G3 TRAEs. The most common TRAEs (any grade/grade ≥3) were AST increased (18%/0%), proteinuria (14%/2%), anemia (14%/2%), and ALT increased (12%/0%). No significant cardiotoxicity or bleeding was observed. GFH018 PK was linear and dose-independent, with a mean half-life of 2.25-8.60 h from 5 - 85 mg. Nine patients (18.0%) achieved stable disease, and one patient with thymic carcinoma achieved tumor shrinkage, with the maximum target lesion decreased by 18.4%. Serum TGF-ß1 levels were not associated with clinical responses. The comprehensive recommended dose for Phase II was defined as 85 mg BID 14d-on/14d-off. CONCLUSIONS: GFH018 monotherapy presented a favorable safety profile without cardiac toxicity or bleeding. Modest efficacy warrants further studies, including combination strategies. TRIAL REGISTRATION: ClinicalTrial. gov ( https://www. CLINICALTRIALS: gov/ ), NCT05051241. Registered on 2021-09-02.

Emerging organophosphite and organophosphate esters in takeaway food and the implications for human exposure.

Takeaway food has become a prominent component of the diet in urban areas of China, especially for young people. Although dietary intake is a major pathway to contaminants for human exposure, studies on emerging organophosphite antioxidants (OPAs) and organophosphate esters (OPEs) in food are scarce. Here, we investigated four OPAs and 19 OPEs in takeaway foods (n = 99) and paired takeaway food packaging (n = 50) in China. AO168=O (mean: 14.9 ng/g ww), TPPO (mean: 1.05 ng/g ww), and TCIPP (mean: 0.579 ng/g ww) were dominant in the takeaway food. Some OPEs had significant correlations in takeaway food. Emerging OPAs and OPEs in takeaway food varied significantly depending on the packaging materials and food types. AO168 and AO168=O were widespread in the paired takeaway food packaging. The migration efficiencies of emerging OPAs and OPEs were low in takeaway food packaged in aluminum foil. Although the actual contamination of emerging OPAs and OPEs in takeaway food significantly differed from those of in food simulants migrated from paired takeaway food packaging, the results imply that food itself and takeaway food packaging are potential contamination sources of emerging OPAs and OPEs in takeaway food. The average estimated dietary intakes of emerging OPAs and OPEs were 465 ng/kg body weight (bw)/day and 91.9 ng/kg bw/day, respectively. The exposure risk of emerging OPAs and OPEs through takeaway food intake is low in China.

Heavy metal induced shifts in microbial community composition and interactions with dissolved organic matter in coastal sediments.

Heavy metals can impact the structure and function of coastal sediment. The dissolved organic matter (DOM) pool plays an important role in determining both the heavy metal toxicity and microbial community composition in coastal sediments. However, how heavy metals affect the interactions between microbial communities and DOM remains unclear. Here, we investigated the influence of heavy metals on the microbial community structure (including bacteria and archaea) and DOM composition in surface sediments of Beibu Gulf, China. Our results revealed firstly that chromium, zinc, cadmium, and lead were the heavy metals contributing to pollution in our studied area. Furthermore, the DOM chemical composition was distinctly different in the contaminated area from the uncontaminated area, characterized by a higher average O/C ratio and increased prevalence of carboxyl-rich alicyclic molecules (CRAM) and highly unsaturated compounds (HUC). This indicates that DOM in the contaminated area was more recalcitrant compared to the uncontaminated area. Except for differences in archaeal diversity between the two areas, there were no significant variations observed in the structure of archaea and bacteria, as well as the diversity of bacteria, across the two areas. Nevertheless, our co-occurrence network analysis revealed that the B2M28 and Euryarchaeota, dominating bacterial and archaeal groups in the contaminated area were strongly related to CRAM. The network analysis also unveiled correlations between active bacteria and elevated proportions of nitrogen-containing DOM molecules. In contrast, the archaea-DOM network exhibited strong associations with nitrogen- and sulfur-containing molecules. Collectively, these findings suggest that heavy metals indeed influence the interaction between microbial communities and DOM, potentially affecting the accumulation of recalcitrant compounds in coastal sediments.

Fabrication of amino- and hydroxyl dual-functionalized magnetic microporous organic network for extraction of zearalenone from traditional Chinese medicine prior to the HPLC determination.

Efficient enrichment of trace zearalenone (ZEN) from the complex traditional Chinese medicine (TCM) samples is quite difficult, but of great significance for TCM quality control. Herein, we reported a novel magnetic solid phase extraction (MSPE) strategy for ZEN enrichment using the amino- and hydroxyl dual-functionalized magnetic microporous organic network (Fe3O4@MON-NH2-OH) as an advanced adsorbent combined with the high-performance liquid chromatography (HPLC) determination. Efficient extraction of ZEN was achieved via the possible hydrogen bonding, hydrophobic, and π-π interactions between Fe3O4@MON-NH2-OH and ZEN. The adsorption capacity of Fe3O4@MON-NH2-OH for ZEN was 215.0 mg g-1 at the room temperature, which was much higher than most of the reported adsorbents. Under the optimal condition, the developed Fe3O4@MON-NH2-OH-MSPE-HPLC method exhibited wide linear range (5-2500 µg L-1), low limits of detection (1.4-35 µg L-1), less adsorbent consumption (5 mg), and large enhancement factor (95) for ZEN. The proposed method was successfully applied to detect trace ZEN from 10 kinds of real TCM samples. Conclusively, this work demonstrates the Fe3O4@MON-NH2-OH can effectively extract trace ZEN from the complex TCM matrices, which may open up a new way for the application of MONs in the enrichment and extraction of trace contaminants or active constituents from the complex TCM samples.

Reconstruction the feedback regulation of amino acid metabolism to develop a non-auxotrophic L-threonine producing Corynebacterium glutamicum.

L-Threonine is an important feed additive with the third largest market size among the amino acids produced by microbial fermentation. The GRAS (generally regarded as safe) industrial workhorse Corynebacterium glutamicum is an attractive chassis for L-threonine production. However, the present L-threonine production in C. glutamicum cannot meet the requirement of industrialization due to the relatively low production level of L-threonine and the accumulation of large amounts of by-products (such as L-lysine, L-isoleucine, and glycine). Herein, to enhance the L-threonine biosynthesis in C. glutamicum, releasing the aspartate kinase (LysC) and homoserine dehydrogenase (Hom) from feedback inhibition by L-lysine and L-threonine, respectively, and overexpressing four flux-control genes were performed. Next, to reduce the formation of by-products L-lysine and L-isoleucine without the cause of an auxotrophic phenotype, the feedback regulation of dihydrodipicolinate synthase (DapA) and threonine dehydratase (IlvA) was strengthened by replacing the native enzymes with heterologous analogues with more sensitive feedback inhibition by L-lysine and L-isoleucine, respectively. The resulting strain maintained the capability of synthesizing enough amounts of L-lysine and L-isoleucine for cell biomass formation but exhibited almost no extracellular accumulation of these two amino acids. To further enhance L-threonine production and reduce the by-product glycine, L-threonine exporter and homoserine kinase were overexpressed. Finally, the rationally engineered non-auxotrophic strain ZcglT9 produced 67.63 g/L (17.2% higher) L-threonine with a productivity of 1.20 g/L/h (108.0% higher) in fed-batch fermentation, along with significantly reduced by-product accumulation, representing the record for L-threonine production in C. glutamicum. In this study, we developed a strategy of reconstructing the feedback regulation of amino acid metabolism and successfully applied this strategy to de novo construct a non-auxotrophic L-threonine producing C. glutamicum. The main end by-products including L-lysine, L-isoleucine, and glycine were almost eliminated in fed-batch fermentation of the engineered C. glutamicum strain. This strategy can also be used for engineering producing strains for other amino acids and derivatives.

Mini-dose methotrexate combined with methylprednisolone for the initial treatment of acute GVHD: a multicentre, randomized trial.

BACKGROUND: There is an urgent unmet need for effective initial treatment for acute graft-versus-host disease (aGVHD) adding to the standard first-line therapy with corticosteroids after allogeneic haematopoietic stem cell transplantation (allo-HSCT). METHODS: We performed a multicentre, open-label, randomized, phase 3 study. Eligible patients (aged 15 years or older, had received allo-HSCT for a haematological malignancy, developed aGVHD, and received no previous therapies for aGVHD) were randomly assigned (1:1) to receive either 5 mg/m2 MTX on Days 1, 3, or 8 and then combined with corticosteroids or corticosteroids alone weekly. RESULTS: The primary endpoint was the overall response rate (ORR) on Day 10. A total of 157 patients were randomly assigned to receive either MTX plus corticosteroids (n = 78; MTX group) or corticosteroids alone (n = 79; control group). The Day 10 ORR was 97% for the MTX group and 81% for the control group (p = .005). Among patients with mild aGVHD, the Day 10 ORR was 100% for the MTX group and 86% for the control group (p = .001). The 1-year estimated failure-free survival was 69% for the MTX group and 41% for the control group (p = .002). There were no differences in treatment-related adverse events between the two groups. CONCLUSIONS: In conclusion, mini-dose MTX combined with corticosteroids can significantly improve the ORR in patients with aGVHD and is well tolerated, although it did not achieve the prespecified 20% improvement with the addition of MTX. TRIAL REGISTRATION: The trial was registered with clinicaltrials.gov (NCT04960644).

Effect of oesophagectomy on lipid profiles in patients with oesophageal cancer combined with hyperlipidaemia: a retrospective study.

BACKGROUND: Surgery is widely regarded as a pivotal therapeutic approach for treating oesophageal cancer, and clinical observations have revealed that many oesophageal cancer patients also present with concomitant hyperlipidaemia. It is surprising that few studies have been performed to determine how blood lipid levels are affected by oesophageal cancer resection. This research was designed to assess the influence of oesophageal cancer resection on lipid profiles among individuals diagnosed with both oesophageal cancer and hyperlipidaemia. METHODS: A retrospective analysis was carried out on 110 patients with hyperlipidaemia and oesophageal cancer who had undergone oesophagectomy at the 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army. Preoperative and postoperative serological data were collected at seven-, thirty-, sixty-day-, and one-year-long intervals. Changes in lipid levels were compared, the remission of various types of hyperlipidaemia was statistically assessed, and Pearson correlation was used to analyse the association between lipid changes and preoperative body weight. The research sought to assess the reduction in body weight and the proportion of body weight lost one year following surgery. RESULTS: Noteworthy decreases were observed in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, with TC decreasing from 6.20 mmol/L to 5.20 mmol/L, TG decreasing from 1.40 mmol/L to 1.20 mmol/L, and LDL decreasing from 4.50 mmol/L to 3.30 mmol/L. Conversely, there was a notable increase in high-density lipoprotein (HDL) levels, which increased from 1.20 mmol/L to 1.40 mmol/L (P < 0.05) compared to the preoperative levels. Notably, the remission rates for mixed hyperlipidaemia (60.9%) and high cholesterol (60.0%) were considerably greater than those for high triglycerides (16.2%). Alterations in TC at one year postoperatively correlated with preoperative weight and weight loss (r = 0.315, -0.216); changes in TG correlated with preoperative weight, percentage of total weight loss (TWL%), and weight reduction (r = -0.295, -0.246, 0.320); and changes in LDL correlated with preoperative weight, TWL%, and weight loss (r = 0.251, 0.186, and -0.207). Changes in non-high-density lipoprotein(non-HDL) were linked to preoperative weight (r = 0.300), and changes in TG/HDL were correlated with preoperative weight and TWL% (r = -0.424, -0.251). CONCLUSIONS: Oesophagectomy significantly improved lipid profiles in oesophageal cancer patients, potentially leading to a reduction in overall cardiovascular risk.

Comparison of condylar position after free fibular flap mandibular reconstruction using computer-assisted and traditional techniques.

OBJECTIVES: To compare the changes in condylar position after mandibular reconstruction with free fibular flap(FFF) and the differences between computer-assisted techniques and traditional methods on CT images. METHODS: Thirty-four patients who underwent mandibular reconstruction with free fibular flap were selected according to the inclusion and exclusion criteria. In the 3D group, virtual surgical planning (VSP) with osteotomy cutting plate and placement guiding plate were used, while the traditional group underwent freehand reconstruction. The CT data of 68 temporomandibular joints (TMJs) were recorded before and immediately after surgery. The condylar position was evaluated by measuring the anterior space (AS), posterior space (PS) and superior space (SS), and the ln (PS/AS) was calculated according to the method proposed by Pullinger and Hollender. RESULTS: In the patients included in the 3D group, the condyle on the ipsilateral side moved slightly backward; however, in the patients in the traditional group, the ipsilateral side moved considerably anteroinferior. No obvious changes on the contralateral side were noted. In the 3D group, 33% of ipsilateral condyles were in the posterior position postoperatively when compared with the preoperative position (13%). In the traditional group, the number of ipsilateral condyles in the anterior position increased from 4 to 10, accounting for 53% postoperatively. Contrary to the traditional group, the 3D group presented less condylar displacement on the ipsilateral side postoperatively. CONCLUSIONS: This study showed a decreased percentage of change in condylar position postoperatively when VSP was used. Virtual surgical planning improved the accuracy of FFF mandibular reconstruction and made the condylar position more stable.

TEC-miTarget: enhancing microRNA target prediction based on deep learning of ribonucleic acid sequences.

BACKGROUND: MicroRNAs play a critical role in regulating gene expression by binding to specific target sites within gene transcripts, making the identification of microRNA targets a prominent focus of research. Conventional experimental methods for identifying microRNA targets are both time-consuming and expensive, prompting the development of computational tools for target prediction. However, the existing computational tools exhibit limited performance in meeting the demands of practical applications, highlighting the need to improve the performance of microRNA target prediction models. RESULTS: In this paper, we utilize the most popular natural language processing and computer vision technologies to propose a novel approach, called TEC-miTarget, for microRNA target prediction based on transformer encoder and convolutional neural networks. TEC-miTarget treats RNA sequences as a natural language and encodes them using a transformer encoder, a widely used encoder in natural language processing. It then combines the representations of a pair of microRNA and its candidate target site sequences into a contact map, which is a three-dimensional array similar to a multi-channel image. Therefore, the contact map's features are extracted using a four-layer convolutional neural network, enabling the prediction of interactions between microRNA and its candidate target sites. We applied a series of comparative experiments to demonstrate that TEC-miTarget significantly improves microRNA target prediction, compared with existing state-of-the-art models. Our approach is the first approach to perform comparisons with other approaches at both sequence and transcript levels. Furthermore, it is the first approach compared with both deep learning-based and seed-match-based methods. We first compared TEC-miTarget's performance with approaches at the sequence level, and our approach delivers substantial improvements in performance using the same datasets and evaluation metrics. Moreover, we utilized TEC-miTarget to predict microRNA targets in long mRNA sequences, which involves two steps: selecting candidate target site sequences and applying sequence-level predictions. We finally showed that TEC-miTarget outperforms other approaches at the transcript level, including the popular seed match methods widely used in previous years. CONCLUSIONS: We propose a novel approach for predicting microRNA targets at both sequence and transcript levels, and demonstrate that our approach outperforms other methods based on deep learning or seed match. We also provide our approach as an easy-to-use software, TEC-miTarget, at https://github.com/tingpeng17/TEC-miTarget . Our results provide new perspectives for microRNA target prediction.

Association between triglyceride glucose and acute kidney injury in patients with acute myocardial infarction: a propensity score­matched analysis.

BACKGROUND: Acute kidney injury (AKI) in patients with acute myocardial infarction (AMI) often indicates a poor prognosis. OBJECTIVE: This study aimed to investigate the association between the TyG index and the risk of AKI in patients with AMI. METHODS: Data were taken from the Medical Information Mart for Intensive Care (MIMIC) database. A 1:3 propensity score (PS) was set to match patients in the AKI and non-AKI groups. Multivariate logistic regression analysis, restricted cubic spline (RCS) regression and subgroup analysis were performed to assess the association between TyG index and AKI. RESULTS: Totally, 1831 AMI patients were included, of which 302 (15.6%) had AKI. The TyG level was higher in AKI patients than in non-AKI patients (9.30 ± 0.71 mg/mL vs. 9.03 ± 0.73 mg/mL, P < 0.001). Compared to the lowest quartile of TyG levels, quartiles 3 or 4 had a higher risk of AKI, respectively (Odds Ratiomodel 4 = 2.139, 95% Confidence Interval: 1.382-3.310, for quartile 4 vs. quartile 1, Ptrend < 0.001). The risk of AKI increased by 34.4% when the TyG level increased by 1 S.D. (OR: 1.344, 95% CI: 1.150-1.570, P < 0.001). The TyG level was non-linearly associated with the risk of AKI in the population within a specified range. After 1:3 propensity score matching, the results were similar and the TyG level remained a risk factor for AKI in patients with AMI. CONCLUSION: High levels of TyG increase the risk of AKI in AMI patients. The TyG level is a predictor of AKI risk in AMI patients, and can be used for clinical management.

L-shaped association between lean body mass to visceral fat mass ratio with hyperuricemia: a cross-sectional study.

BACKGROUND: Insufficient attention has been given to examining the correlation between body composition and hyperuricemia, leading to inconsistent findings. The primary objective of this research is to explore the association between lean body mass index (LMI), visceral fat mass index (VFMI), and hyperuricemia. A specific emphasis will be placed on assessing the link between the ratio of lean body mass to visceral fat mass (LMI/VFMI) and hyperuricemia. METHODS: The present study employed a cross-sectional design and involved a total of 9,646 individuals who participated in the National Health and Nutrition Examination Survey (NHANES). To explore the associations among the variables, logistic and linear regressions were employed. Additionally, subgroup analyses and sensitivity analyses were conducted based on various characteristics. RESULTS: The results showed that LMI was positively associated with hyperuricemia (for Per-SD: OR = 1.88, 95%CI: 1.75, 2.01; for quartiles [Q4:Q1]: OR = 5.37, 95%CI: 4.31, 6.69). Meanwhile, VFMI showed a positive association with hyperuricemia (for Per-SD: OR = 2.02, 95%CI: 1.88, 2.16; for quartiles [Q4:Q1]: OR =8.37, 95%CI: 6.70, 10.47). When considering the effects of In LMI/VFMI, an L-shaped negative association with hyperuricemia was observed (for Per-SD: OR = 0.45, 95%CI: 0.42, 0.49; for quartiles [Q4:Q1]: OR = 0.16, 95%CI: 0.13, 0.20). Subgroup and sensitivity analyses demonstrated the robustness of this association across different subgroups. Additionally, the segmented regression analysis indicated a saturation effect of 5.64 for the In LMI/VFMI with hyperuricemia (OR = 0.20, 95%CI: 0.17, 0.24). For every 2.72-fold increase of In LMI/VFMI, the risk of hyperuricemia was reduced by 80%. CONCLUSION: The LMI/VFMI ratio is non-linearly associated with serum uric acid. Whether this association is causal needs to be confirmed in further longitudinal studies or Mendelian randomization.

Development and validation of the hospice professional coping scale among Chinese nurses.

BACKGROUND: Hospice care professionals often experience trauma patient deaths and multiple patient deaths in a short period of time (more so than other nurses). This repeated exposure to the death process and the death of patients leads to greater psychological pressure on hospice care professionals. But at present, people pay more attention to the feelings and care burden of the family members of dying patients but pay less attention to medical staff. Thus, this study aimed to develop a scale on the burden of care for hospice care providers and assess the coping capacity of hospice professionals. Raising awareness of the psychological burden of hospice professionals. METHODS: Through a literature review, research group discussion, Delphi method and a pre-survey of professional coping skills among nurses, 200 hospice professionals who had received training in hospice care from pilot institutions engaged in or providing hospice care were selected for investigation. Cronbach's α coefficient and split-half reliability were used to test the internal consistency of the scale, and content validity and explore factor analysis (EFA) were used to test the construct validity of the scale. RESULTS: Two rounds of Delphi methods were carried out, and the effective recovery rate was 100%. The expert authority coefficients of the two rounds were 0.838 and 0.833, respectively. The Kendall's W coefficient of experts in the first round was 0.121 ~ 0.200 (P < 0.05), and the Kendall's W coefficient of the second round was 0.115-0.136 (P < 0.05), indicating a good level of expert coordination. The final survey scale for the care burden of hospice professionals included four dimensions-working environment (9 items), professional roles (8 items), clinical nursing (9 items) and psychological burden (7 items)-with a total of 33 items. The total Cronbach's α coefficient of the scale was 0.963, and the Cronbach's α coefficients of the working environment, professional roles, clinical nursing and psychological burden dimensions were 0.920, 0.889, 0.936 and 0.910, respectively. The total split-half reliability of the scale was 0.927, and the split-half reliability of each dimension was 0.846, 0.817, 0.891, and 0.832. The content validity of the scale items ranged from 0.90 to 1.00. Exploratory factor analysis revealed 5 common factors, with a total cumulative contribution rate of 68.878%. The common degree of each item in the scale was > 0.4, and the factor loading of each item was also > 0.4. CONCLUSION: The scale is an open-access, short, easy-to-administer scale. And which for assessing hospice care burden among hospice professionals developed in this study demonstrated strong reliability and validity. This tool can serve as a dependable instrument for evaluating the burden of hospice care for terminally ill patients by professionals in the hospice setting.

Evaluation of Peregrinus maidis transformer-2 as a target for CRISPR-based control.

The corn planthopper, Peregrinus maidis, is an economically important pest of corn and sorghum. Here we report the initial steps towards developing a CRISPR-based control method, precision guided sterile insect technique (pgSIT), for this hemipteran pest. Specifically, we evaluated the potential of transformer-2 (tra-2) as a target for sterilizing insects. First, we identified tra-2 transcripts within our P. maidis transcriptome database and performed RNA interference (RNAi) to confirm functional conservation. RNAi-mediated knockdown of Pmtra-2 in nymphs transformed females into pseudomales with deformed ovipositors resembling male claspers. While males showed no overt difference in appearance, they were indeed sterile. Importantly, the results were similar to those observed in another planthopper, Nilaparvata lugens. We also used CRISPR/Cas9 genome editing to assess the impact of tra-2 knockout in injectees. CRISPR-mediated knockout of Pmtra-2 had lethal effects on embryos, and hence not many injectees reached adulthood. However, mosaic knockout of Pmtra-2 did impact female and male fertility, which supports the use of tra-2 as a target for pgSIT in this hemipteran species.

Understanding Senior Adults' Needs, Preferences, and Experiences of Commercial Exergames for Health: Usability Study.

BACKGROUND: Many senior adults are at risk of mental and physical disorders due to a lack of sufficient exercise. Therefore, adherent exercise should be urgently promoted to improve senior adults' muscle strength, preventing falls and conditions caused by physical and cognitive decline. However, off-the-shelf exercise games, so-called exergames, are mainly targeted at the younger generation or children, while senior adults are neglected, when this age group strongly needs exercise. Exergames could serve as a health intervention for promoting exercise. OBJECTIVE: This study aimed to investigate senior adults' experience, perceptions, and acceptance of game technology to promote exercise in order to suggest game design guidelines. METHODS: In this usability study, participants engaged in playing Nintendo Switch and Xbox Kinect games, after which semistructured interviews were conducted. Before the gameplay, the participants provided their background information, exercise habits, and use of technology products. Next, all participants completed a workshop including 3 activities (brief instructions on how to play the games: 20 minutes; playing the selected exergames: 80 minutes; semistructured interviews: 20 minutes) for 2 hours a day for 3 days each. The participants played the latest Nintendo Switch games (eg, Just Dance, Boxing, Ring Fit Adventure) and Xbox Kinect games (eg, Kinect Adventures!, Mini Games). Just Dance, Zumba, and Boxing were played in activity 1; Ring Fit Adventure and Mini Games in activity 2; and Kinect Adventures! in activity 3. Reflexive thematic analysis was applied to identify the relative themes generated from the interviews. RESULTS: In total, 22 participants (mean age 70.4, SD 6.1 years) were enrolled in the workshop in May 2021. The results of the generated themes included incomprehension of game instructions, psychological perception of game technology, and game art preferences. The subthemes generated from game art preferences included favorite game genres, characters, and scenes. CONCLUSIONS: There is a significant need for customized game tutorials considering senior adults' cognitive and physical aging. Furthermore, the adventure game genre is preferable to other games. Humanlike game characters are preferable, especially those with a fit and healthy body shape. Nature scenes are more enjoyable than indoor stages or rooms. Furthermore, the game intensity design and playing time should be carefully planned to meet the World Health Organization's criteria for physical activity in older adults. Intelligent recommendation systems might be helpful to support older adults with various health conditions. The guidelines suggested in this study might be beneficial for game design, exercise training, and game technology adoption of exergames for older adults to improve health.

Heterogeneous Rhodium Single-Atom-Site Catalyst Enables Chemoselective Carbene N-H Bond Insertion.

Transition-metal-catalyzed carbene insertion reactions of a nitrogen-hydrogen bond have emerged as robust and versatile methods for the construction of C-N bonds. While significant progress of homogeneous catalytic metal carbene N-H insertions has been achieved, the control of chemoselectivity in the field remains challenging due to the high electrophilicity of the metal carbene intermediates. Herein, we present an efficient strategy for the synthesis of a rhodium single-atom-site catalyst (Rh-SA) that incorporates a Rh atom surrounded by three nitrogen atoms and one phosphorus atom doped in a carbon support. This Rh-SA catalyst, with a catalyst loading of only 0.15 mol %, exhibited exceptional catalytic performance for heterogeneous carbene insertion with various anilines and heteroaryl amines in combination with diazo esters. Importantly, the heterogeneous catalyst selectively transformed aniline derivatives bearing multiple nucleophilic moieties into single N-H insertion isomers, while the popular homogeneous Rh2(OAc)4 catalyst produced a mixture of overfunctionalized side products. Additionally, similar selectivities for N-H bond insertion with a set of stereoelectronically diverse diazo esters were obtained, highlighting the general applicability of this heterogeneous catalysis approach. On the basis of density functional theory calculations, the observed selectivity of the Rh-SA catalyst was attributed to the insertion barriers and the accelerated proton transfer assisted by the phosphorus atom in the support. Overall, this investigation of heterogeneous metal-catalyzed carbene insertion underscores the potential of single-atom-site catalysis as a powerful and complementary tool in organic synthesis.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. METHODS: Hepatic SHP knockout mice (SHPΔhep) and their wild-type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPΔhep mice were reconstituted with bone marrow lacking interferon γ (IFNγ-/-) to suppress inflammation. RESULTS: Hepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPΔhep mice. The increased inflammation and fibrosis in SHPΔhep mice were corrected with bone marrow-derived IFNγ-/- myeloid cell transplantation. CONCLUSION: Hepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro-MASH pathways. The IFNγ-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH.

Positive Regulatory Roles of Manihot esculenta HAK5 under K+ Deficiency or High Salt Stress.

HAK/KUP/KT family members have been identified as playing key roles in K+ uptake and salt tolerance in numerous higher plants. However, their functions in cassava (Manihot esculenta Cantz) remain unknown. In this study, a gene encoding for a high-affinity potassium transporter (MeHAK5) was isolated from cassava and its function was investigated. Subcellular localization analysis showed that MeHAK5 is a plasma membrane-localized transporter. RT-PCR and RT-qPCR indicated that MeHAK5 is predominantly expressed in cassava roots, where it is upregulated by low potassium or high salt; in particular, its highest expression levels separately increased by 2.2 and 2.9 times after 50 µM KCl and 150 mM NaCl treatments. When heterologously expressed in yeast, MeHAK5 mediated K+ uptake within the cells of the yeast strain CY162 and rescued the salt-sensitive phenotype of AXT3K yeast. MeHAK5 overexpression in transgenic Arabidopsis plants exhibited improved growth and increased shoot K+ content under low potassium conditions. Under salt stress, MeHAK5 transgenic Arabidopsis plants accumulated more K+ in the shoots and roots and had reduced Na+ content in the shoots. As a result, MeHAK5 transgenic Arabidopsis demonstrated a more salt-tolerant phenotype. These results suggest that MeHAK5 functions as a high-affinity K+ transporter under K+ starvation conditions, improving K+/Na+ homeostasis and thereby functioning as a positive regulator of salt stress tolerance in transgenic Arabidopsis. Therefore, MeHAK5 may be a suitable candidate gene for improving K+ utilization efficiency and salt tolerance.

Somatomotor-visual resting state functional connectivity increases after 2 years in the UK Biobank longitudinal cohort.

Purpose: Functional magnetic resonance imaging (fMRI) and functional connectivity (FC) have been used to follow aging in both children and older adults. Robust changes have been observed in children, in which high connectivity among all brain regions changes to a more modular structure with maturation. We examine FC changes in older adults after 2 years of aging in the UK Biobank (UKB) longitudinal cohort. Approach: We process fMRI connectivity data using the Power264 atlas and then test whether the average internetwork FC changes in the 2722-subject longitudinal cohort are statistically significant using a Bonferroni-corrected t-test. We also compare the ability of Power264 and UKB-provided, independent component analysis (ICA)-based FC to determine which of a longitudinal scan pair is older. Finally, we investigate cross-sectional FC changes as well as differences due to differing scanner tasks in the UKB, Philadelphia Neurodevelopmental Cohort, and Alzheimer's Disease Neuroimaging Initiative datasets. Results: We find a 6.8% average increase in somatomotor network (SMT)-visual network (VIS) connectivity from younger to older scans (corrected p<10-15) that occurs in male, female, older subject (>65 years old), and younger subject (<55 years old) groups. Among all internetwork connections, the average SMT-VIS connectivity is the best predictor of relative scan age. Using the full FC and a training set of 2000 subjects, one is able to predict which scan is older 82.5% of the time using either the full Power264 FC or the UKB-provided ICA-based FC. Conclusions: We conclude that SMT-VIS connectivity increases with age in the UKB longitudinal cohort and that resting state FC increases with age in the UKB cross-sectional cohort.

Muscular Function Recovery from General Anesthesia in 132 Patients Undergoing Surgery with Acceleromyography, Combined Acceleromyography, and Ultrasonography, and without Monitoring Muscular Function.

BACKGROUND Diaphragmatic thickness fraction (DTF), measured by ultrasound, can predict the occurrence of postoperative residual neuromuscular blockade (RNMB). We hypothesized that the utilization of diaphragmatic ultrasound during the postoperative awakening phase of anesthesia in patients offers a successful means of avoiding RNMB in a notably comfortable manner, as compared to the use of acceleromyograph. MATERIAL AND METHODS Patients who underwent elective thyroid cancer radical surgery were enrolled in this prospective clinical study. Eligible participants were randomly assigned to 1 of 3 groups: 1) combined ultrasonography with acceleromyography group (the US+AMG group), 2) the AMG group, or 3) the usual clinical practice group (the UCP group). The primary outcomes of the study were the incidence of RNMB and hypoxemia after tracheal extubation. RESULTS The study included a total of 127 patients (43 in the US+AMG group, 44 in the AMG group, and 40 in the UCP group). The incidence of RNMB and hypoxemia was higher in the UCP group than in the US+AMG and AMG groups at 15 and 30 min after extubation, respectively. The mean area under the receiver operating characteristic curve, and the decision curve of the recovery rate of DTF (DTF) was greater than that of DTF. CONCLUSIONS The use of diaphragm ultrasound during the postoperative awakening phase of anesthesia can significantly reduce the incidence of RNMB. This method was non-inferior to the use of AMG during the entire perioperative period.

Dry and liquid formulations of IBT-V02, a novel multi-component toxoid vaccine, are effective against Staphylococcus aureus isolates from low-to-middle income countries.

Staphylococcus aureus is the leading cause of skin and soft tissue infections (SSTIs) in the U.S. as well as more serious invasive diseases, including bacteremia, sepsis, endocarditis, surgical site infections, osteomyelitis, and pneumonia. These infections are exacerbated by the emergence of antibiotic-resistant clinical isolates such as methicillin-resistant S. aureus (MRSA), highlighting the need for alternatives to antibiotics to treat bacterial infections. We have previously developed a multi-component toxoid vaccine (IBT-V02) in a liquid formulation with efficacy against multiple strains of Staphylococcus aureus prevalent in the industrialized world. However, liquid vaccine formulations are not compatible with the paucity of cold chain storage infrastructure in many low-to-middle income countries (LMICs). Furthermore, whether our IBT-V02 vaccine formulations are protective against S. aureus isolates from LMICs is unknown. To overcome these limitations, we developed lyophilized and spray freeze-dried formulations of IBT-V02 vaccine and demonstrated that both formulations had comparable biophysical attributes as the liquid formulation, including similar levels of toxin neutralizing antibodies and protective efficacy against MRSA infections in murine and rabbit models. To enhance the relevancy of our findings, we then performed a multi-dimensional screen of 83 S. aureus clinical isolates from LMICs (e.g., Democratic Republic of Congo, Palestine, and Cambodia) to rationally down-select strains to test in our in vivo models based on broad expression of IBT-V02 targets (i.e., pore-forming toxins and superantigens). IBT-V02 polyclonal antisera effectively neutralized toxins produced by the S. aureus clinical isolates from LMICs. Notably, the lyophilized IBT-V02 formulation exhibited significant in vivo efficacy in various preclinical infection models against the S. aureus clinical isolates from LMICs, which was comparable to our liquid formulation. Collectively, our findings suggested that lyophilization is an effective alternative to liquid vaccine formulations of our IBT-V02 vaccine against S. aureus infections, which has important implications for protection from S. aureus isolates from LMICs.