The emergence of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) variants has altered the trajectory of the COVID‐19 pandemic and raised some uncertainty on the long‐term efficiency of ...vaccine strategy. The development of new therapeutics against a wide range of SARS‐CoV‐2 variants is imperative. We, here, have designed an inhalable siRNA, C6G25S, which covers 99.8% of current SARS‐CoV‐2 variants and is capable of inhibiting dominant strains, including Alpha, Delta, Gamma, and Epsilon, at picomolar ranges of IC50 in vitro. Moreover, C6G25S could completely inhibit the production of infectious virions in lungs by prophylactic treatment, and decrease 96.2% of virions by cotreatment in K18‐hACE2‐transgenic mice, accompanied by a significant prevention of virus‐associated extensive pulmonary alveolar damage, vascular thrombi, and immune cell infiltrations. Our data suggest that C6G25S provides an alternative and effective approach to combating the COVID‐19 pandemic.
Synopsis
C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration.
A broadly active siRNA covers 99.8% of SARS‐CoV‐2 variants, including highly infective Delta and Omicron.
C6G25S completely inhibited the Delta variant in lungs of infected mice by prophylactic treatment and decreased 93% of virions by co‐treatment.
First study that use fully modified siRNA for inhalation and achieved promising therapeutic effect without a special delivery system.
C6G25S is a safe, effective, and feasible therapeutic approach that could reach the market in a short time.
C6G25S is a fully modified siRNA specifically targeting the highly‐conserve region of SARS‐CoV‐2 genome. It has been developed as an inhalable and broad‐spectrum therapeutic that is highly stable and effective via direct respiratory administration.
Conventional cytogenetics can categorize patients with acute myeloid leukemia (AML) into favorable, intermediate, and unfavorable‐risk groups; however, patients with intermediate‐risk cytogenetics ...represent the major population with variable outcomes. Because molecular profiling can assist with AML prognosis and next‐generation sequencing allows simultaneous sequencing of many target genes, we analyzed 260 genes in 112 patients with de novo AML who received standard treatment. Multivariate analysis showed that karyotypes and mutation status of TET2, PHF6, KIT, and NPM1mutation/FLT3‐ internal tandem duplication (ITD)negative were independent prognostic factors for the entire cohort. Among patients with intermediate‐risk cytogenetics, patients with mutations in CEBPAdouble mutation, IDH2, and NPM1 in the absence of FLT3‐ITD were associated with improved Overall survival (OS), similar to those with favorable‐risk cytogenetics; patients with mutations in TET2, RUNX1, ASXL1, and DNMT3A were associated with reduced OS, similar to those with unfavorable‐risk cytogenetics. We concluded that integration of cytogenetic and molecular profiling improves prognostic stratification of patients into three groups with more distinct prognoses (P < 0.001) and significantly reduces the number of patients classified as intermediate risk. In addition, our study demonstrates that next‐generation sequencing (NGS)‐based multi‐gene sequencing is clinically applicable in establishing an accurate risk stratification system for guiding therapeutic decisions.
We comprehensively analyzed 260 genes by next‐generation sequencing (NGS) in 112 patients with de novo acute myeloid leukemia (AML). Our result suggested that parallel sequencing using NGS was a good strategy to handle the testing of multiple genes and could provide a rapid and accurate risk classification system for the clinical management of AML patients.
Antibiotic resistance genes (ARGs) in urban rivers are a serious public health concern in regions with poorly planned, rapid development. To gain insights into the predominant factors affecting the ...fate of ARGs in a highly polluted urban river in eastern China, a total of 285 ARGs, microbial communities, and 20 physicochemical parameters were analyzed for 17 sites. A total of 258 unique ARGs were detected using high-throughput qPCR, and the absolute abundance of total ARGs was positively correlated with total organic carbon and total dissolved nitrogen concentrations (
P
< 0.01). ARG abundance and diversity were greatly altered by microbial community structure. Variation partitioning analysis showed that the combined effects of multiple factors contributed to the profile and dissemination of ARGs, and variation of microbial communities was the major factor affecting the distribution of ARGs. The disparate distribution of some bacteria, including
Bacteroides
from mammalian gastrointestinal flora,
Burkholderia
from zoonotic infectious diseases, and
Zoogloea
from wastewater treatment, indicates that the urban river was strongly influenced by point-source pollution. Results imply that microbial community shifts caused by changes in water quality may lead to the spread of ARGs, and point-source pollution in urban rivers requires greater attention to control the transfer of ARGs between environmental bacteria and pathogens.
During the near‐infrared spectroscopy analysis process, modeling the quantitative relationship between the collected spectral information and target components is an important procedure. Before using ...the traditional modeling methods, it is often necessary to select the most featured wavelengths and eliminate those uninformative wavelengths. However, the wavelength selection algorithms can not only increase the model complexity but also may contain some adjustable parameters, which need the users to have more expertise knowledge and experiences. To solve this problem, this paper proposed a novel end‐to‐end quantitative analysis modeling method for near‐infrared spectroscopy based on convolutional neural network (CNN), which directly takes the whole range of collected raw spectral information as input without wavelength selection. The public corn NIR dataset was taken as example to validate the efficiency of proposed method. The experimental results showed that, firstly, if all the whole range of raw spectral information was taken as the input of modeling, the generalized performance of CNN outperforms the traditional methods, and the difference is statistically significant; secondly, if the traditional methods were combined with wavelength selection algorithms, their generalized performances were similar to CNN model; there is no statistical difference. The results indicated that applying the deep learning methods (take CNN as representative) to establish the quantitative analysis model of near‐infrared spectroscopy is easy to use and has more potential popularize values.
A novel end‐to‐end quantitative analysis modeling method for infrared spectroscopy is proposed based on convolutional neural network (CNN), which can directly take the whole range of collected raw spectral information as input without wavelength selection. The experimental results indicated that applying the deep learning methods (take CNN as representative) to establish the quantitative analysis model of near infrared spectroscopy is easy to use and has more potential popularize values.
2D organic-inorganic lead iodide perovskites have recently received tremendous attention as promising light absorbers for solar cells, due to their excellent optoelectronic properties, structural ...tunability, and environmental stability. However, although great efforts have been made, no 2D lead iodide perovskites have been discovered as ferroelectrics, in which the ferroelectricity may improve the photovoltaic performance. Here, by incorporating homochiral cations, 2D lead iodide perovskite ferroelectrics R-1-(4-chlorophenyl)ethylammonium
PbI
and S-1-(4-chlorophenyl)ethylammonium
PbI
are successfully obtained. The vibrational circular dichroism spectra and crystal structural analysis reveal their homochirality. They both crystalize in a polar space group P1 at room temperature, and undergo a 422F1 type ferroelectric phase transition with transition temperature as high as 483 and 473.2 K, respectively, showing a multiaxial ferroelectric nature. They also possess semiconductor characteristics with a direct bandgap of 2.34 eV. Nevertheless, their racemic analogue adopts a centrosymmetric space group P2
/c at room temperature, exhibiting no high-temperature phase transition. The homochirality in 2D lead iodide perovskites facilitates crystallization in polar space groups. This finding indicates an effective way to design high-performance 2D lead iodide perovskite ferroelectrics with great application prospects.
Introduction
Severe spinal cord injury results in the loss of neurons in the relatively intact spinal cord below the injury area and skeletal muscle atrophy in the paralyzed limbs. These pathological ...processes are significant obstacles for motor function reconstruction.
Objective
We performed tail nerve electrical stimulation (TNES) to activate the motor neural circuits below the injury site of the spinal cord to elucidate the regulatory mechanisms of the excitatory afferent neurons in promoting the reconstruction of locomotor function.
Methods
Eight days after T10 spinal cord transection in rats, TNES was performed for 7 weeks. Behavioral scores were assessed weekly. Electrophysiological tests and double retrograde tracings were performed at week 8.
Results
After 7 weeks of TNES treatment, there was restoration in innervation, the number of stem cells, and mitochondrial metabolism in the rats' hindlimb muscles. Double retrograde tracings of the tail nerve and sciatic nerve further confirmed the presence of synaptic connections between the tail nerve and central pattern generator (CPG) neurons in the lumbar spinal cord, as well as motor neurons innervating the hindlimb muscles.
Conclusion
The mechanisms of TNES induced by the stimulation of primary afferent nerve fibers involves efficient activation of the motor neural circuits in the lumbosacral segment, alterations of synaptic plasticity, and the improvement of muscle and nerve regeneration, which provides the structural and functional foundation for the future use of cutting‐edge biological treatment strategies to restore voluntary movement of paralyzed hindlimbs.
The specific neural pathway and the mechanism of activation in the spinal cord CPG and effects on the motor neural circuits during TNES treatment.
Dysregulated maternal nutrition, such as vitamin deficiencies and excessive levels of glucose and fatty acids, increases the risk for congenital heart disease (CHD) in the offspring. However, the ...association between maternal amino‐acid levels and CHD is unclear. Here, it is shown that increased leucine levels in maternal plasma during the first trimester are associated with elevated CHD risk in the offspring. High levels of maternal leucine increase embryonic lysine‐leucylation (K‐Leu), which is catalyzed by leucyl‐tRNA synthetase (LARS). LARS preferentially binds to and catalyzes K‐Leu modification of lysine 339 within T‐box transcription factor TBX5, whereas SIRT3 removes K‐Leu from TBX5. Reversible leucylation retains TBX5 in the cytoplasm and inhibits its transcriptional activity. Increasing embryonic K‐Leu levels in high‐leucine‐diet fed or Sirt3 knockout mice causes CHD in the offspring. Targeting K‐Leu using the leucine analogue leucinol can inhibit LARS activity, reverse TBX5 K‐Leu modification, and decrease the occurrence of CHD in high‐leucine‐diet fed mice. This study reveals that increased maternal leucine levels increases CHD risk in the offspring through inhibition of embryonic TBX5 signaling, indicating that leucylation exerts teratogenic effects during heart development and may be an intervening target of CHD.
Increased gestational leucine levels are significantly associated with risk for congenital heart disease (CHD) in offspring. Increased embryonic lysine‐leucylation (K‐Leu), generated via maternal high‐leucine‐chow feeding, or Sirt3 knockout, causes CHD in the offspring of mice, through elevating embryonic K‐Leu of TBX5 and inhibiting TBX5 activity. Targeting K‐Leu via leucinol reverses K‐Leu modifications and lowers the occurrence of CHD in mice.
Phthalocyanines are potentially promising photosensitizers (PSs) for photodynamic therapy (PDT), but the inherent defects such as aggregation-caused quenching effects and non-specific toxicity ...severely hinder their further application in PDT. Herein, we synthesized two zinc(II) phthalocyanines (PcSA and PcOA) monosubstituted with a sulphonate group in the alpha position with "O bridge" and "S bridge" as bonds and prepared a liposomal nanophotosensitizer (PcSA@Lip) by thin-film hydration method to regulate the aggregation of PcSA in the aqueous solution and enhance its tumor targeting ability. PcSA@Lip exhibited highly efficient production of superoxide radical (O
) and singlet oxygen (
O
) in water under light irradiation, which were 2.6-fold and 15.4-fold higher than those of free PcSA, respectively. Furthermore, PcSA@Lip was able to accumulate selectively in tumors after intravenous injection with the fluorescence intensity ratio of tumors to livers was 4.1:1. The significant tumor inhibition effects resulted in a 98% tumor inhibition rate after PcSA@Lip was injected intravenously at an ultra-low PcSA@Lip dose (0.8 nmol g
PcSA) and light dose (30 J cm
). Therefore, the liposomal PcSA@Lip is a prospective nanophotosensitizer possessing hybrid type I and type II photoreactions with efficient photodynamic anticancer effects.
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