Case report: Fatal Legionella infection diagnosed via by metagenomic next-generation sequencing in a patient with chronic myeloid leukemia.

Legionella is an aerobic, gram-negative, intracellular pathogen and is an important cause of community-acquired pneumonia. Legionella pneumophila is the most common causative agent of Legionella pneumonia. Clinical diagnosis of Legionella pneumonia is challenging due to the lack of specific clinical manifestations and the low positive rates of conventional pathogen detection methods. In this study, we report a case of a patient with chronic myeloid leukemia who developed rigors and high fever after chemotherapy and immunotherapy. Chest computed tomography revealed consolidation in the left lower lobe of the lung and ground-glass opacities in both lower lobes. Multiple blood cultures showed Escherichia coli, Staphylococcus aureus, Bacillus licheniformis, and positive results in the ß-D-glucan test (G test). The patient was treated with various sensitive antimicrobial agents, including meropenem plus fluconazole, meropenem plus carpofungin, and vancomycin. Unfortunately, the patient's condition gradually worsened and eventually resulted in death. On the following day of death, metagenomic next-generation sequencing (mNGS) of 1whole blood revealed L. pneumophila pneumonia with concurrent bloodstream infection (blood mNGS reads 114,302). These findings suggest that when conventional empirical antimicrobial therapy proves ineffective for critically ill patients with pneumonia, the possibility of combined Legionella infection must be considered, and mNGS can provide a diagnostic tool in such cases.

A Homo-Mannich Reaction Strategy Enables Collective Access to Ibophyllidine, Aspidosperma, Kopsia, and Melodinus Alkaloids.

We report here a homo-Mannich reaction of cyclopropanol with an iminium ion, generated by an asymmetric allylic dearomatization of indole, to construct a tricyclic hydrocarbazole core, which is shared by a variety of monoterpenoid indole alkaloids across families. Through this approach, an all-carbon quaternary stereogenic center as well as an allyl and a ketone group were installed. Using this functionalized hydrocarbazole as the structural platform, D ring and E rings of different sizes (i.e., five-, six-, and seven-membered) were successively or simultaneously assembled, leading to a collective asymmetric synthesis of seven alkaloids belonging to the ibophyllidine, Aspidosperma, Kopsia, and Melodinus alkaloid families.

YOLO-FR: A YOLOv5 Infrared Small Target Detection Algorithm Based on Feature Reassembly Sampling Method.

The loss of infrared dim-small target features in the network sampling process is a major factor affecting its detection accuracy. In order to reduce this loss, this paper proposes YOLO-FR, a YOLOv5 infrared dim-small target detection model, based on feature reassembly sampling, which refers to scaling the feature map size without increasing or decreasing the current amount of feature information. In this algorithm, an STD Block is designed to reduce the loss of features during down-sampling by saving spatial information to the channel dimension, and the CARAFE operator, which increases the feature map size without changing the feature mapping mean, is adopted to ensure that features are not distorted by relational scaling. In addition, in order to make full use of the detailed features extracted by the backbone network, the neck network is improved in this study so that the feature extracted after one down-sampling of the backbone network is fused with the top-level semantic information by the neck network to obtain the target detection head with a small receptive field. The experimental results show that the YOLO-FR model proposed in this paper achieved 97.4% on mAP50, which is a 7.4% improvement compared to the original network, and it also outperformed J-MSF and YOLO-SASE.

Thermal-Resistance Effect of Graphene at High Temperatures in Nanoelectromechanical Temperature Sensors.

Graphene membranes act as temperature sensors in nanoelectromechanical devices due to their excellent thermal and high-temperature resistance properties. Experimentally, reports on the sensing performance of graphene mainly focus on the temperature interval under 400 K. To explore the sensing performance of graphene temperature sensors at higher temperature intervals, micro-fabricated single-layer graphene on a SiNX substrate is presented as temperature sensors by semiconductor technology and its electrical properties were measured. The results show that the temperature coefficient of the resistance value is 2.07 × 10-3 in the temperature range of 300-450 K and 2.39 × 10-3 in the temperature range of 450-575 K. From room temperature to high temperature, the "metal" characteristics are presented, and the higher TCR obtained at higher temperature interval is described and analyzed by combining Boltzmann transport equation and thermal expansion theory. These investigations provide further insight into the temperature characteristics of graphene.

Development of highly potent non-covalent inhibitors of SARS-CoV-2 3CLpro

The SARS-CoV-2 virus is the causal agent of the ongoing pandemic of coronavirus disease 2019 (COVID-19). There is an urgent need for potent, specific antiviral compounds against SARS-CoV-2. The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses, and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, non-covalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment. One-Sentence SummaryA oral non-covalent inhibitor of 3C-like protease effectively inhibits SARS-CoV-2 replication.

YOLO-SASE: An Improved YOLO Algorithm for the Small Targets Detection in Complex Backgrounds.

To improve the detection ability of infrared small targets in complex backgrounds, an improved detection algorithm YOLO-SASE is proposed in this paper. The algorithm is based on the YOLO detection framework and SRGAN network, taking super-resolution reconstructed images as input, combined with the SASE module, SPP module, and multi-level receptive field structure while adjusting the number of detection output layers through exploring feature weight to improve feature utilization efficiency. Compared with the original model, the accuracy and recall rate of the algorithm proposed in this paper were improved by 2% and 3%, respectively, in the experiment, and the stability of the results was significantly improved in the training process.

Asymmetric Total Syntheses of Schizozygane Alkaloids.

The concise, collective, and asymmetric total syntheses of four schizozygane alkaloids, which feature a "Pan lid"-like hexacyclic core scaffold bearing up to six continuous stereocenters, including two quaternary ones, are described. A new method of dearomative cyclization of cyclopropanol onto the indole ring at C2 was developed to build the ABCF ring system of the schizozygane core with a ketone group. Another key skeleton-building reaction, the Heck/carbonylative lactamization cascade, ensured the rapid assembly of the hexacyclic schizozygane core and concurrent installation of an alkene group. By strategic use of these two reactions and through late-stage diversifications of the functionalized schizozygane core, the first and asymmetric total syntheses of (+)-schizozygine, (+)-3-oxo-14α,15α-epoxyschizozygine, and (+)-α-schizozygol and the total synthesis of (+)-strempeliopine have been accomplished in 11-12 steps from tryptamines.

Long-Term Effects of Climate and Competition on Radial Growth, Recovery, and Resistance in Mongolian Pines.

Understanding the response of tree growth and drought vulnerability to climate and competition is critical for managing plantation forests. We analyzed the growth of Mongolian pines in six forests planted by the Three-North Shelter Forest Program with tree-ring data and stand structures. A retroactive reconstruction method was used to depict the growth-competition relationships of Mongolian pines during the growth period and their climatic responses under different competition levels. Drought vulnerability was analyzed by measuring the basal area increment (BAI) of different competition indices (CIs). In young trees, differences in BAIs in stands with different CIs were not statistically significant. After 15-20 years, medium- and high-CI stands had significantly lower tree-ring widths (TWs) and BAIs than the low-CI stands (p < 0.05). The standardized precipitation evapotranspiration index (SPEI), precipitation, relative humidity, and vapor pressure deficit were major factors affecting tree growth. On a regional scale, climate outweighed competition in determining radial growth. The relative contribution of climatic factors increased with the gap in SPEI between plantation sites and the native range, while the reverse pattern of the competition-growth relationship was observed. Drought reduced TWs and BAIs at all sites. Stands of different CIs exhibited similar resistance, but, compared with low-CI stands, high- and medium-CI stands had significantly lower recovery, resilience, and relative resilience, indicating they were more susceptible to drought stresses. Modeled CI was significantly negatively related to resistance, resilience, and relative resilience, indicating a density-dependence of tree response to drought. After exposure to multiple sequential drought events, the relative resilience of high-CI stands decreased to almost zero; this failure to fully recover to pre-drought growth rates suggests increased mortality in the future. In contrast, low-CI stands are more likely to survive in hotter, more arid climates. These results provide a better understanding of the roles of competition and climate on the growth of Mongolian pines and offer a new perspective for investigating the density-dependent recovery and resilience of these forests.

Circulating glutathione peroxidase and superoxide dismutase levels in patients with epilepsy: A meta-analysis.

PURPOSE: Glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) are assessed as oxidative stress markers to determine the impact of oxidation on the levels of GSH-Px and SOD in patients with epilepsy (PWE) and healthy controls. METHODS: A meta-analysis was completed on twenty-nine published studies. A total of 636 PWE and 665 healthy controls, 303 PWE and 191 controls, and 22 PWE and 22 controls were included to study GSH-Px levels in erythrocytes, serum and plasma, respectively. For SOD studies, there were 610 PWE and 680 controls, 464 PWE and 382 controls, and 62 PWE with 77 controls for erythrocytes, serum and plasma, respectively. RESULTS: Meta-analysis showed that the erythrocyte SOD level was significantly lower in PWE than in healthy controls (SMD =-1.96; 95% CI [-2.93, -0.99]; P<0.0001). Moreover, the meta-analysis demonstrated that in serum and plasma, SOD levels in PWE were significantly lower than those in healthy controls (SMD =-1.47; 95% CI [-2.47, -0.48]; P<0.0001). Erythrocyte GSH-Px levels had a tendency to decrease in PWE compared with healthy controls (SMD =-0.31; 95% CI [-1.48, 0.85]; P=0.598), but the results showed no significant difference. CONCLUSION: Our results showed reduced SOD levels in erythrocytes, serum and plasma in PWE, which may be an indicator of oxidative damage in epilepsy. This is the first meta-analysis of circulating GSH-Px and SOD levels in PWE and healthy controls.

The Preclinical Inhibitor GS441524 in Combination with GC376 Efficaciously Inhibited the Proliferation of SARS-CoV-2 in the Mouse Respiratory Tract

The unprecedented coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a serious threat to global public health. Development of effective therapies against SARS-CoV-2 is urgently needed. Here, we evaluated the antiviral activity of a remdesivir parent nucleotide analog, GS441524, which targets the coronavirus RNA-dependent RNA polymerase enzyme, and a feline coronavirus prodrug, GC376, which targets its main protease, using a mouse-adapted SARS-CoV-2 infected mouse model. Our results showed that GS441524 effectively blocked the proliferation of SARS-CoV-2 in the mouse upper and lower respiratory tracts via combined intranasal (i.n.) and intramuscular (i.m.) treatment. However, the ability of high-dose GC376 (i.m. or i.n. and i.m.) was weaker than GS441524. Notably, low-dose combined application of GS441524 with GC376 could effectively protect mice against SARS-CoV-2 infection via i.n. or i.n. and i.m. treatment. Moreover, we found that the pharmacokinetic properties of GS441524 is better than GC376, and combined application of GC376 and GS441524 had a synergistic effect. Our findings support the further evaluation of the combined application of GC376 and GS441524 in future clinical studies. ImportanceSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has seriously threatened global public health and economic development. Currently, effective therapies to treat COVID-19 are urgently needed. In this study, we assessed the efficacy of the preclinical inhibitors GC376 and GS441524 using a mouse-adapted SARS-CoV-2 infected mouse model for the first time. Our results showed that low-dose combined application of GC376 and GS441524 could effectively protect mice from HRB26M infection in the upper and lower respiratory tracts. Hence, the combined application should be developed and considered for future clinic practice.

Sustained increased CaMKII phosphorylation is involved in the impaired regression of isoproterenol-induced cardiac hypertrophy in rats.

To understand the mechanism underlying the regression of cardiac hypertrophy, we investigated the pathological changes after isoproterenol (ISO) withdrawal in ISO-induced cardiomyopathy models in rats and neonatal cardiomyocytes. Cardiac hypertrophy was induced in rats by two weeks of ISO administration; however, the hypertrophy did not regress after three weeks of natural maintenance after ISO administration was withdrawn (ISO-wdr group). The remaining hypertrophy in the ISO-wdr group was accompanied by a sustained increase in the level of phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII). Additionally, the increased expression levels of histone deacetylase 4 (HDAC4) and the CaV1.2 channel and amounts of CaMKII bound with HDAC4 and CaV1.2 were not recovered in the ISO-wdr group. The results in cardiomyocyte models were similar to those seen in rat models. Losartan, metoprolol or amlodipine neither ameliorated the increase in atrial natriuretic peptide nor inhibited the increase in p-CaMKII and bound CaMKII. In contrast, autocamtide-2-related inhibitor peptide, a CaMKII inhibitor, reduced these increases. This study investigated the phosphorylation status of CaMKII after hypertrophic stimulus was withdrawn for the first time and proposed that CaMKII as well as its complexes with CaV1.2 could be potential targets to achieve effective regression of cardiac hypertrophy.

Distinct roles of calmodulin and Ca2+/calmodulin-dependent protein kinase II in isopreterenol-induced cardiac hypertrophy.

Intracellular calcium is related to cardiac hypertrophy. The CaV1.2 channel and Ca2+/calmodulin-dependent protein kinase II (CaMKII) and CaM regulate the intracellular calcium content. However, the differences in CaMKII and CaM in cardiac hypertrophy are still conflicting and are worthy of studying as drug targets. Therefore, in this study, we aim to investigate the roles and mechanism of CaM and CaMKII on CaV1.2 in pathological myocardial hypertrophy. The results showed that ISO stimulation caused SD rat heart and cardiomyocyte hypertrophy. In vivo, the HW/BW, LVW/BW, cross-sectional area, fibrosis ratio and ANP expression were all increased. There were no differences in CaV1.2 channel expression in the in vivo model or the in vitro model, but the ISO stimulation induced channel activity, and the [Ca2+]i increased. The protein expression levels of CaMKII and p-CaMKII were all increased in the ISO group, but the CaM expression level decreased. AIP inhibited ANP, CaMKII and p-CaMKII expression, and ISO-induced [Ca2+]i increased. AIP also reduced HDAC4, p-HDAC and MEF2C expression. However, CMZ did not play a cardiac hypertrophy reversal role in vitro. In conclusion, we considered that compared with CaM, CaMKII may be a much more important drug target in cardiac hypertrophy reversal.

[Differences in atmospheric CO2 concentration and δ13C value between green spaces and its adjacent roads as well as the influencing factors in Beijing, China.] / 北京城市绿地与周边道路空气CO2浓度和δ13Cå€¼çš„å·®å¼‚åŠå½±å“å› ç´ .

Near-surface atmospheric CO2 concentration and δ13C value in four greenspaces and on their adjacent roads in Beijing were measured by off-axis integrated cavity output spectroscopy to analyze the influence of urban greenspace on spatial distribution of near-surface atmospheric CO2. The results showed that atmospheric CO2 concentration and δ13C value varied substantially both temporally and spatially. The highest CO2 concentration was found in the urban area, followed by the suburbs, and the lowest CO2 concentration was in the outer suburbs. There was a clear near-surface atmospheric CO2 dome, but a reverse pattern for δ13C value. During the non-growing season, the ΔCO2 and Δ13C between greenspace and adjacent roads were low. The differences among the four experimental sites were not significant. In the growing season, the ΔCO2 and Δ13C at the BLA4th RR (Beijing Institute of Landscape Architecture and 4th Ring Road) and BOP5th RR (Beijing Olympic Forest Park and 5th Ring Road) in urban areas were significantly higher than those at DPSR (Daoxianghu Park and Sujiatuo Road) and MTGMR (Mentougou forest experimental station and an adjacent road) in the suburbs. During the growing and non-growing seasons, CO2 concentration of all examined sites was significantly positively related with the traffic volume, indicating that traffic volume was an important factor affecting the spatial distribution of CO2. The δ13C value was significantly negatively related with traffic volume during non-growing season, but no significant relationship was found during the growing season. The ΔCO2 concentration between the four green-spaces and their adjacent roads were significantly negatively related with leaf area index (LAI). The Δ13C value were significantly logarithmically related to LAI. Results from stepwise regression showed that solar radiation, temperature, and LAI significantly affected ΔCO2 in urban areas and suburbs during the growing season, and that temperature and solar radiation were the major driving factors for Δ13C. During the growing season, plants in the greenspaces assimilated CO2 via photosynthesis and thus reduced the near-surface atmospheric CO2 concentration. Our results indicate that green-spaces play a positive role in improving ecological environment in urban areas.

Brønsted Base-Switched Selective Mono- and Dithiolation of Benzamides via Copper Catalysis.

A versatile protocol for the direct thiolation of an inert sp2 C-H bond is presented via a catalytic amount of copper catalysis, by switching related Brønsted bases and regulating the reaction time, and the corresponding mono- and dithiolation products can be obtained selectively in moderate to good yields. The reaction exhibits a relatively broad substrate scope and a good functional group tolerance, even with different heterocyclic amides and alkyl thiols.

Synthesis of α-arylthioacetones using TEMPO as the C3 synthon via a reaction cascade of sequential oxidation, skeletal rearrangement and C-S bond formation.

Here, we present an unprecedented pathway to α-sulfenylated carbonyl compounds from commercially available thiols and universally employed TEMPO and its analogues, which act as C3 synthons through skeletal rearrangement under simple and metal-free conditions. Mechanism studies suggest that this reaction involves a consecutive radical oxidation and cation coupling process. TEMPO analogues and thiols serve as oxidants and reductive reagents, respectively, along the radical process, while in the coupling process, the former ones afford C3 synthons to couple with related sulfur sources.

A concise synthesis and biological study of evodiamine and its analogues.

Efficient access to evodiamine and its analogues is presented via Lewis acid catalysis. In this reaction, three chemical bonds and two heterocyclic-fused rings are constructed in one step. The reaction shows good functional group tolerance and atom economy, and various heteroatom-containing evodiamine analogues are obtained in moderate to excellent yields even on a gram scale. An anti-tumor study in vitro demonstrates compound 2b possesses potent efficacy against hepatoma cell line (IC50 = 5.7 µM).

Chimeric rabies glycoprotein with a transmembrane domain and cytoplasmic tail from Newcastle disease virus fusion protein incorporates into the Newcastle disease virion at reduced levels

Rabies remains an important worldwide health problem. Newcastle disease virus (NDV) was developed as a vaccine vector in animals by using a reverse genetics approach. Previously, our group generated a recombinant NDV (LaSota strain) expressing the complete rabies virus G protein (RVG), named rL-RVG. In this study, we constructed the variant rL-RVGTM, which expresses a chimeric rabies virus G protein (RVGTM) containing the ectodomain of RVG and the transmembrane domain (TM) and a cytoplasmic tail (CT) from the NDV fusion glycoprotein to study the function of RVG's TM and CT. The RVGTM did not detectably incorporate into NDV virions, though it was abundantly expressed at the surface of infected BHK-21 cells. Both rL-RVG and rL-RVGTM induced similar levels of NDV virus-neutralizing antibody (VNA) after initial and secondary vaccination in mice, whereas rabies VNA induction by rL-RVGTM was markedly lower than that induced by rL-RVG. Though rL-RVG could spread from cell to cell like that in rabies virus, rL-RVGTM lost this ability and spread in a manner similar to the parental NDV. Our data suggest that the TM and CT of RVG are essential for its incorporation into NDV virions and for spreading of the recombinant virus from the initially infected cells to surrounding cells.

Far field 3D localization of radioactive hot spots using a coded aperture camera.

This paper presents a coded aperture method to remotely estimate the radioactivity of a source. The activity is estimated from the detected counts and the estimated source location, which is extracted by factoring the effect of aperture magnification. A 6mm thick tungsten-copper alloy coded aperture mask is used to modulate the incoming gamma-rays. The location of point and line sources in all three dimensions was estimated with an accuracy of less than 10% when the source-camera distance was about 4 m. The estimated activities were 17.6% smaller and 50.4% larger than the actual activities for the point and line sources, respectively.