Capreomycidine (Cap) is a nonproteinogenic amino acid and building block of nonribosomal peptide (NRP) natural products. We report the formation and activation of Cap in capreomycin biosynthesis. ...CmnC and CmnD catalyzed hydroxylation and cyclization, respectively, of l-Arg to form l-Cap. l-Cap is then adenylated by CmnG-A before being incorporated into the nonribosomal peptide. The co-crystal structures of CmnG-A with l-Cap and adenosine nucleotides provide insights into the specificity and engineering opportunities of this unique adenylation domain.
: Walking while performing cognitive and motor tasks simultaneously interferes with gait performance and may lead to falls in older adults with mild cognitive impairment (MCI). Executive function, ...which seems to play a key role in dual-task gait performance, can be improved by combined physical and cognitive training. Virtual reality (VR) has the potential to assist rehabilitation, and its effect on physical and cognitive function requires further investigation. The purpose of this study was to assess the effects of VR-based physical and cognitive training on executive function and dual-task gait performance in older adults with MCI, as well as to compare VR-based physical and cognitive training with traditional combined physical and cognitive training.
: Thirty-four community-dwelling older adults with MCI were randomly assigned into either a VR-based physical and cognitive training (VR) group or a combined traditional physical and cognitive training (CPC) group for 36 sessions over 12 weeks. Outcome measures included executive function Stroop Color and Word Test (SCWT) and trail making test (TMT) A and B, gait performance (gait speed, stride length, and cadence) and dual-task costs (DTCs). Walking tasks were performed during single-task walking, walking while performing serial subtraction (cognitive dual task), and walking while carrying a tray (motor dual task). The GAIT Up system was used to evaluate gait parameters including speed, stride length, cadence and DTCs. DTC were defined as 100 * (single-task gait parameters - dual-task gait parameters)/single-task gait parameters.
: Both groups showed significant improvements in the SCWT and single-task and motor dual-task gait performance measures. However, only the VR group showed improvements in cognitive dual-task gait performance and the DTC of cadence. Moreover, the VR group showed more improvements than the CPC group in the TMT-B and DTC of cadence with borderline significances.
: A 12-week VR-based physical and cognitive training program led to significant improvements in dual-task gait performance in older adults with MCI, which may be attributed to improvements in executive function.
Host cell proteins (HCPs) are process-related impurities that are generated by the host organism and are typically present at low levels in recombinant biopharmaceutical products, such as therapeutic ...antibodies. While overall HCP levels are usually monitored by enzyme-linked immunosorbent assay (ELISA), liquid chromatography coupled to mass spectrometry (LC-MS) is emerging as a powerful tool that can provide both qualitative and quantitative information about HCP levels during purification process development. However, a major challenge for LC-MS-based methods is that there can be a more than 5 orders of magnitude difference in the concentration between HCPs and therapeutic antibody in solution, which precludes the effective identification of low abundance HCPs in antibody product. This work reports a simple and powerful strategy to identify HCPs in antibody drug substance by applying molecular weight cutoff (MWCO) filtration step followed by shotgun proteomic analysis. After dissociating the interaction between HCPs and antibody with an anionic detergent, the depletion of antibody from HCPs can be easily achieved with the MWCO filtration step. Using this method, we observed that the dynamic range across proteins in the HCP samples was significantly decreased up to 1000-fold. In addition, by spiking in known amounts of HCPs to purified antibody drug substance with low levels of HCPs, we demonstrated that our method could detect HCP with low molecular weight (11 kDa and 17 kDa) at a concentration as low as 1 ppm. When applying this methodology to the study of HCPs in NIST monoclonal antibody (NISTmAb), more than 150 HCPs were confidently identified, which doubles the number of identified HCPs that have been previously reported. Parallel reaction monitoring (PRM) results confirmed that the novel HCPs found using this method were present in very low abundance (0.01–8 ppm), highlighting that our method reduces the dynamic range by removing antibody interference and improving the sensitivity of HCP identification and quantification.
This study is the first to use reliable data sources to establish a reasonable mass balance of Cr(VI) contamination in river water, sediment, and farmland soil. A system dynamics model was used to ...establish the interrelationships among water, Cr(VI) contamination, and health effects in the Wu River watershed (between Taichung city and Changhua county) between 2018 and 2048 (30 years). The results show very little Cr(VI) contamination in rivers; most flowed downstream or settled in sediment, and the accumulation of Cr(VI) in the sediment increased throughout the study period. The highest Cr(VI) concentrations in farmland soil (338.46 mg/kg) were reached in Changhua county as a result of greater Cr(VI) contamination from upstream and local factories. This Cr(VI) contamination led to gastric cancer risks of 5.24 × 10−4 and 4.38 × 10−6 in Changhua county and Taichung city, respectively. Although most of the Cr(VI) contamination was discharged from Taichung City, greater health risks and losses occurred downstream in Changhua county; medical costs were 55 times higher. For total quality control, a reduction rate of at least 68% should be reached in the study area. These findings will be helpful in predicting the transmission of Cr(VI) contamination over long study periods with a systematic model.
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•This study establish a reasonable mass balance of Cr(VI) contamination in river water, sediment, and soil.•Very little Cr(VI) contamination in rivers; most flowed downstream or settled in sediment.•Cr(VI) contamination led to gastric cancer risks of 5.24 × 10−4–4.38 × 10−6 in Taiwan.•For total quality control, a reduction rate of at least 68% should be reached in the study area.
The development of high performance, stable catalyst with non-precious metals for electrochemical hydrogen evolution reaction for alkaline electrolysis is in demand. Here-in, we report the synthesis ...of CuFe layered double hydroxide (LDH) electrocatalyst on nickel foam via facile hydrothermal method. In alkaline electrolysis with 1 M NaOH electrolyte, CuFe LDH as cathode requires an overpotential of 159 mV to generate current density of 10 mA cm−2. Which is ca. 51 mV and 7 mV lower than NiFe LDH and NiRu LDH. CuFe LDH exhibits significant electrocatalytic activity for HER. The higher catalytic activity of CuFe LDH compared to NiFe LDH may be achieved with higher proton adsorption by Cu compared to Ni. Also, the efficient charge transfer with interconnected LDH layers, favourable three dimensional structure facilitating easy electrolyte transfer to the active sites and hydrogen gas diffusion. This work may help in developing low cost and efficient hydroxide catalyst.
•CuFe layered double hydroxide is prepared by hydrothermal process.•Synthesis of low cost and non-precious metal electrocatalyst for electrolysis.•CuFe LDH/Ni electrocatalyst requires only 159 mV at 10 mA cm−2 in HER.•Stable after 5 h chronopotentiometry test.
Aging leads to decreased skeletal muscle function in mammals and is associated with a progressive loss of muscle mass, quality and strength. Age-related muscle loss (sarcopenia) is an important ...health problem associated with the aged population.
We investigated the alteration of genome-wide transcription in mouse skeletal muscle tissue (rectus femoris muscle) during aging using a high-throughput sequencing technique. Analysis revealed significant transcriptional changes between skeletal muscles of mice at 3 (young group) and 24 (old group) months of age. Specifically, genes associated with energy metabolism, cell proliferation, muscle myosin isoforms, as well as immune functions were found to be altered. We observed several interesting gene expression changes in the elderly, many of which have not been reported before.
Those data expand our understanding of the various compensatory mechanisms that can occur with age, and further will assist in the development of methods to prevent and attenuate adverse outcomes of aging.
Genetic research on influenza virus biology has been informed in large part by nucleotide variants present in seasonal or pandemic samples, or individual mutants generated in the laboratory, leaving ...a substantial part of the genome uncharacterized. Here, we have developed a single-nucleotide resolution genetic approach to interrogate the fitness effect of point mutations in 98% of the amino acid positions in the influenza A virus hemagglutinin (HA) gene. Our HA fitness map provides a reference to identify indispensable regions to aid in drug and vaccine design as targeting these regions will increase the genetic barrier for the emergence of escape mutations. This study offers a new platform for studying genome dynamics, structure-function relationships, virus-host interactions, and can further rational drug and vaccine design. Our approach can also be applied to any virus that can be genetically manipulated.
Intestinal homeostasis depends on interactions between the intestinal epithelium, the immune system and the microbiota. Because of these complicated connections, there are many problems that need to ...be solved. Current research has indicated that genes targeted by Wnt signaling are responsible for controlling intestinal stem cell fate and for modulating intestinal homeostasis. Our data show that loss of frizzled 7 (Fzd7), an important element in Wnt signaling, interrupts the differentiation of mouse intestinal stem cells into absorptive progenitors instead of secretory progenitors (precursors of goblet and Paneth cells). The alteration in canonical Wnt and Notch signaling pathways interrupts epithelial homeostasis, resulting in a decrease in physical protection in the intestine. Several phenotypes in our Fzd7-deleted model were similar to the features of enterocolitis, such as shortened intestines, decreased numbers of goblet cells and Paneth cells, and severe inflammation. Additionally, loss of Fzd7 exacerbated the defects in a chemical-induced colitis model and could initiate tumorigenesis. These findings may provide important information for the discovery of efficient therapeutic methods to treat enterocolitis and related cancers in the intestines.
Accumulating evidence suggests the involvement of tumor-derived exosomes in the development and recurrence of hepatocellular carcinoma (HCC). We previously identified miR-4669 as a highly expressed ...microRNA in circulating exosomes obtained from patients with post-transplant HCC recurrence. This study aimed to explore how overexpression of miR-4669 affects HCC development and recurrence. The impact of miR-4669 overexpression in Hep3B cells on tumor cell behavior and the tumor microenvironment was evaluated in vitro. In addition, the clinical value of exosomal miR-4669 for the prediction of treatment response to HCC downstaging therapies and following post-transplant HCC recurrence was explored. Overexpression of miR-4669 enhanced migration ability and led to acquired sorafenib resistance with an elevation of sirtuin 1 and long noncoding RNA associated with microvascular invasion. Active release of tumor-derived exosomes and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) contributed to generating an immunosuppressive tumor microenvironment through the induction of M2 macrophage polarization. The retrospective analysis demonstrated the clinical value of exosomal miR-4669 for predicting treatment response to HCC downstaging therapies and for risk assessment of post-transplant HCC recurrence. In summary, the present data demonstrate the impact of exosomal miR-4669 on HCC recurrence through the enhancement of tumor aggressiveness and generation of an immunosuppressive tumor microenvironment.
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