A Novel Whole-Cell Biocatalyst with NAD+ Regeneration for Production of Chiral Chemicals

Background: The high costs of pyridine nucleotide cofactors have limited the applications of NAD(P)-dependent oxidoreductases on an industrial scale. Although NAD(P)H regeneration systems have been widely studied, NAD(P) + regeneration, which is required in reactions where the oxidized form of the cofactor is used, has been less well explored, particularly in whole-cell biocatalytic processes. Methodology/Principal Findings: Simultaneous overexpression of an NAD + dependent enzyme and an NAD + regenerating enzyme (H2O producing NADH oxidase from Lactobacillus brevis) in a whole-cell biocatalyst was studied for application in the NAD +-dependent oxidation system. The whole-cell biocatalyst with (2R,3R)-2,3-butanediol dehydrogenase as the catalyzing enzyme was used to produce (3R)-acetoin, (3S)-acetoin and (2S,3S)-2,3-butanediol. Conclusions/Significance: A recombinant strain, in which an NAD + regeneration enzyme was coexpressed, displayed significantly higher biocatalytic efficiency in terms of the production of chiral acetoin and (2S,3S)-2,3-butanediol. The application of this coexpression system to the production of other chiral chemicals could be extended by using differen

Elevated serum platelet count inhibits the effects of brain functional changes on cognitive function in patients with mild cognitive impairment: A resting-state functional magnetic resonance imaging study

ObjectiveBrain function remodeling has been observed in patients with mild cognitive impairment (MCI) and is closely associated with cognitive performance. However, it is not clear if this relationship is influenced by complete blood counts. This study investigated the role of complete blood counts in the relationship between brain function and cognitive performance.MethodsTwenty-two MCI patients and eighteen controls were enrolled. All subjects underwent resting-state functional magnetic resonance imaging. A neuropsychological battery [Mini-Mental Status Examination, Auditory Verbal Learning Test (AVLT), Symbol Digit Modalities Test, Boston Naming Test (BNT), Shape Trails Test B (STT-B), Rey Complex Figure Test (RCFT), Hamilton Anxiety Rating Scale (HAMA), and Hamilton Depression Scale] was used to assess cognitive function, and MCI patients received complete blood counts tests for red blood cells (RBC), white blood cells, hemoglobin (HGB), monocytes, and platelet counts (PLT).ResultsCompared with controls, MCI patients demonstrated significantly decreased amplitude of low-frequency fluctuation (ALFF) values in the left dorsolateral superior frontal gyrus, left post orbitofrontal cortex, right medial superior frontal gyrus, right insula, and left triangular inferior frontal gyrus. In the MCI group, there were associations between ALFF values of the left hippocampus (HIP.L) and AVLT (p = 0.003) and AVLT-N5 scores (p = 0.001); ALFF values of the right supramarginal gyrus (SMG.R) and BNT scores (p = 0.044); ALFF values of the right superior temporal gyrus (STG.R) and BNT scores (p = 0.022); ALFF values of the left precuneus (PCUN.L) and STT-B time (p = 0.012); and ALFF values of the left caudate nucleus (CAU.L) and RCFT-time (p = 0.036). Moreover, the HAMA scores were negatively correlated with RBC and HGB levels, and positively correlated with monocyte count. The PLT count was positively correlated with STT-B time. Additionally, high PLT count inhibited the effect of ALFF values of the PCUN. L on STT-B performance in MCI patients (p = 0.0207).ConclusionALFF values of the HIP. L, SMG.R, STG. R, PCUN.L, and CAU. L were associated with decreased memory, language, executive function, and visuospatial ability in MCI patients. Notably, elevated PLT count could inhibit the effect of brain functional changes in the PCUN.L on executive function in MCI patients

Oral vinorelbine and continuous low doses of cyclophosphamide in pediatric rhabdomyosarcoma: a real-world study

Introduction: Metronomic maintenance therapy (MMT) has significantly improved the survival of patients with high-risk rhabdomyosarcoma in clinical trials. However, there remains a lack of relevant data on its effectiveness in real-world situations.Methods: We retrospectively retrieved data of 459 patients < 18 years of age diagnosed with rhabdomyosarcoma at Sun Yat-sen University Cancer Center from January 2011 to July 2020 from our database. The MMT regimen was oral vinorelbine 25–40 mg/m2 for twelve 4-week cycles on days 1, 8, and 15, and oral cyclophosphamide 25–50 mg/m2 daily for 48 consecutive weeks.Results: A total of 57 patients who underwent MMT were included in the analysis. The median follow-up time was 27.8 (range: 2.9–117.5) months. From MMT to the end of follow-up, the 3-year PFS and OS rates were 40.6% ± 6.8% and 58.3% ± 7.2%, respectively. The 3-year PFS was 43.6% ± 11.3% in patients who were initially diagnosed as low- and intermediate-risk but relapsed after comprehensive treatment (20/57), compared with 27.8% ± 10.4% in high-risk patients (20/57) and 52.8% ± 13.3% in intermediate-risk patients who did not relapse (17/57). The corresponding 3-year OS for these three groups was 65.8% ± 11.4%, 50.1% ± 12.9%, and 55.6% ± 13.6%, respectively.Conclusion: We present a novel study of MMT with oral vinorelbine and continuous low doses of cyclophosphamide in real-world pediatric patients with RMS. Our findings showed that the MMT strategy significantly improved patient outcomes and may be an effective treatment for high-risk and relapsed patients

Evolution of Antibody Immunity to SARS-CoV-2

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected 78 million individuals and is responsible for over 1.7 million deaths to date. Infection is associated with development of variable levels of antibodies with neutralizing activity that can protect against infection in animal models. Antibody levels decrease with time, but the nature and quality of the memory B cells that would be called upon to produce antibodies upon re-infection has not been examined. Here we report on the humoral memory response in a cohort of 87 individuals assessed at 1.3 and 6.2 months after infection. We find that IgM, and IgG anti-SARS-CoV-2 spike protein receptor binding domain (RBD) antibody titers decrease significantly with IgA being less affected. Concurrently, neutralizing activity in plasma decreases by five-fold in pseudotype virus assays. In contrast, the number of RBD-specific memory B cells is unchanged. Memory B cells display clonal turnover after 6.2 months, and the antibodies they express have greater somatic hypermutation, increased potency and resistance to RBD mutations, indicative of continued evolution of the humoral response. Analysis of intestinal biopsies obtained from asymptomatic individuals 4 months after coronavirus disease-2019 (COVID-19) onset, using immunofluorescence, or polymerase chain reaction, revealed persistence of SARS-CoV-2 nucleic acids and immunoreactivity in the small bowel of 7 out of 14 volunteers. We conclude that the memory B cell response to SARS-CoV-2 evolves between 1.3 and 6.2 months after infection in a manner that is consistent with antigen persistence

Charged Particle Tracking in Real-Time Using a Full-Mesh Data Delivery Architecture and Associative Memory Techniques

We present a flexible and scalable approach to address the challenges of charged particle track reconstruction in real-time event filters (Level-1 triggers) in collider physics experiments. The method described here is based on a full-mesh architecture for data distribution and relies on the Associative Memory approach to implement a pattern recognition algorithm that quickly identifies and organizes hits associated to trajectories of particles originating from particle collisions. We describe a successful implementation of a demonstration system composed of several innovative hardware and algorithmic elements. The implementation of a full-size system relies on the assumption that an Associative Memory device with the sufficient pattern density becomes available in the future, either through a dedicated ASIC or a modern FPGA. We demonstrate excellent performance in terms of track reconstruction efficiency, purity, momentum resolution, and processing time measured with data from a simulated LHC-like tracking detector

China’s 10-year progress in DC gas-insulated equipment: From basic research to industry perspective

The construction of the future energy structure of China under the 2050 carbon-neutral vision requires compact direct current (DC) gas-insulation equipment as important nodes and solutions to support electric power transmission and distribution of long-distance and large-capacity. This paper reviews China's 10-year progress in DC gas-insulated equipment. Important progresses in basic research and industry perspective are presented, with related scientific issues and technical bottlenecks being discussed. The progress in DC gas-insulated equipment worldwide (Europe, Japan, America) is also reported briefly

Recent Progress and Next Steps for the MATHUSLA LLP Detector

We report on recent progress and next steps in the design of the proposed MATHUSLA Long Lived Particle (LLP) detector for the HL-LHC as part of the Snowmass 2021 process. Our understanding of backgrounds has greatly improved, aided by detailed simulation studies, and significant R&D has been performed on designing the scintillator detectors and understanding their performance. The collaboration is on track to complete a Technical Design Report, and there are many opportunities for interested new members to contribute towards the goal of designing and constructing MATHUSLA in time for HL-LHC collisions, which would increase the sensitivity to a large variety of highly motivated LLP signals by orders of magnitude.Comment: Contribution to Snowmass 2021 (EF09, EF10, IF6, IF9), 18 pages, 12 figures. v2: included additional endorser

CATMoS: Collaborative Acute Toxicity Modeling Suite.

BACKGROUND: Humans are exposed to tens of thousands of chemical substances that need to be assessed for their potential toxicity. Acute systemic toxicity testing serves as the basis for regulatory hazard classification, labeling, and risk management. However, it is cost- and time-prohibitive to evaluate all new and existing chemicals using traditional rodent acute toxicity tests. In silico models built using existing data facilitate rapid acute toxicity predictions without using animals. OBJECTIVES: The U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) Acute Toxicity Workgroup organized an international collaboration to develop in silico models for predicting acute oral toxicity based on five different end points: Lethal Dose 50 (LD50 value, U.S. Environmental Protection Agency hazard (four) categories, Globally Harmonized System for Classification and Labeling hazard (five) categories, very toxic chemicals [LD50 (LD50≤50mg/kg)], and nontoxic chemicals (LD50>2,000mg/kg). METHODS: An acute oral toxicity data inventory for 11,992 chemicals was compiled, split into training and evaluation sets, and made available to 35 participating international research groups that submitted a total of 139 predictive models. Predictions that fell within the applicability domains of the submitted models were evaluated using external validation sets. These were then combined into consensus models to leverage strengths of individual approaches. RESULTS: The resulting consensus predictions, which leverage the collective strengths of each individual model, form the Collaborative Acute Toxicity Modeling Suite (CATMoS). CATMoS demonstrated high performance in terms of accuracy and robustness when compared with in vivo results. DISCUSSION: CATMoS is being evaluated by regulatory agencies for its utility and applicability as a potential replacement for in vivo rat acute oral toxicity studies. CATMoS predictions for more than 800,000 chemicals have been made available via the National Toxicology Program's Integrated Chemical Environment tools and data sets (ice.ntp.niehs.nih.gov). The models are also implemented in a free, standalone, open-source tool, OPERA, which allows predictions of new and untested chemicals to be made. https://doi.org/10.1289/EHP8495

Optimasi Portofolio Resiko Menggunakan Model Markowitz MVO Dikaitkan dengan Keterbatasan Manusia dalam Memprediksi Masa Depan dalam Perspektif Al-Qur`an

Risk portfolio on modern finance has become increasingly technical, requiring the use of sophisticated mathematical tools in both research and practice. Since companies cannot insure themselves completely against risk, as human incompetence in predicting the future precisely that written in Al-Quran surah Luqman verse 34, they have to manage it to yield an optimal portfolio. The objective here is to minimize the variance among all portfolios, or alternatively, to maximize expected return among all portfolios that has at least a certain expected return. Furthermore, this study focuses on optimizing risk portfolio so called Markowitz MVO (Mean-Variance Optimization). Some theoretical frameworks for analysis are arithmetic mean, geometric mean, variance, covariance, linear programming, and quadratic programming. Moreover, finding a minimum variance portfolio produces a convex quadratic programming, that is minimizing the objective function ðð¥with constraintsð ð 𥠥 ðandð´ð¥ = ð. The outcome of this research is the solution of optimal risk portofolio in some investments that could be finished smoothly using MATLAB R2007b software together with its graphic analysis

Impacts of the Tropical Pacific/Indian Oceans on the Seasonal Cycle of the West African Monsoon

The current consensus is that drought has developed in the Sahel during the second half of the twentieth century as a result of remote effects of oceanic anomalies amplified by local land–atmosphere interactions. This paper focuses on the impacts of oceanic anomalies upon West African climate and specifically aims to identify those from SST anomalies in the Pacific/Indian Oceans during spring and summer seasons, when they were significant. Idealized sensitivity experiments are performed with four atmospheric general circulation models (AGCMs). The prescribed SST patterns used in the AGCMs are based on the leading mode of covariability between SST anomalies over the Pacific/Indian Oceans and summer rainfall over West Africa. The results show that such oceanic anomalies in the Pacific/Indian Ocean lead to a northward shift of an anomalous dry belt from the Gulf of Guinea to the Sahel as the season advances. In the Sahel, the magnitude of rainfall anomalies is comparable to that obtained by other authors using SST anomalies confined to the proximity of the Atlantic Ocean. The mechanism connecting the Pacific/Indian SST anomalies with West African rainfall has a strong seasonal cycle. In spring (May and June), anomalous subsidence develops over both the Maritime Continent and the equatorial Atlantic in response to the enhanced equatorial heating. Precipitation increases over continental West Africa in association with stronger zonal convergence of moisture. In addition, precipitation decreases over the Gulf of Guinea. During the monsoon peak (July and August), the SST anomalies move westward over the equatorial Pacific and the two regions where subsidence occurred earlier in the seasons merge over West Africa. The monsoon weakens and rainfall decreases over the Sahel, especially in August.Peer reviewe