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"Tao, Yun"
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Bones of the earth
Bones of the Earth is Edgar Award-winning author Eliot Pattison's much anticipated tenth and final installment in the internationally acclaimed Inspector Shan series. After Shan Tao Yun is forced to witness the execution of a Tibetan for corruption, he can't shake the suspicion that he has instead witnessed a murder arranged by conspiring officials. When he learns that a Tibetan monk has been accused by the same officials of using Buddhist magic to murder soldiers then is abruptly given a badge as special deputy to the county governor, Inspector Shan realizes he is being thrust into a ruthless power struggle. Knowing he has made too many enemies in the government, Shan desperately wants to avoid such a battle, but then discovers that among its casualties are a murdered American archaeology student and devout Tibetans who were only trying to protect an ancient shrine. Soon grasping that the underlying mysteries are rooted in both the Chinese and Tibetan worlds, Shan senses that he alone may be able to find the truth. The path he must take, with the enigmatic, vengeful father of the dead American at his side, is the most treacherous he has ever navigated. More will die before he is able to fully pierce the secrets of this clash between the angry gods of Tibet and Beijing. The costs to Shan and those close to him will be profoundly painful, and his world will be shaken to its core before he crafts his own uniquely Tibetan form of justice.
Book
Preclinical development of a microRNA-based therapy for intervertebral disc degeneration
Understanding the molecular mechanisms regulating the maintenance and destruction of intervertebral disc may lead to the development of new therapies for intervertebral disc degeneration (IDD). Here we present evidence from miRNA microarray analyses of clinical data sets along with in vitro and in vivo experiments that miR-141 is a key regulator of IDD. Gain- and loss-of-function studies show that miR-141 drives IDD by inducing nucleus pulposus (NP) apoptosis. Furthermore, miR-141 KO in mice attenuated spontaneous and surgically induced IDD. Mechanistically, miR-141 promotes IDD development by targeting and depleting SIRT1, a negative regulator of NF-κB pathway. Therapeutically, upregulation or downregulation of miR-141 by nanoparticle delivery in IDD model aggravated or alleviated experimental IDD, respectively. Our findings reveal a novel mechanism by which miR-141, in part, promotes IDD progression by interacting with SIRT1/NF-κB pathway. Blockade of miR-141 in vivo may serve as a potential therapeutic approach in the treatment of IDD.
Intervertebral disk degeneration (IDD) is characterized by changes in the nucleus pulposus (NP) extra cellular matrix that compromise disk structural integrity. In a miRNA screen of human IDD patient NP tissue, the authors identify deregulated miR-141 and show that direct injection of nanoparticle-coupled miR-141 into the NP alleviates IDD in mice.
Journal Article
Isotropic reconstruction for electron tomography with deep learning
Cryogenic electron tomography (cryoET) allows visualization of cellular structures in situ. However, anisotropic resolution arising from the intrinsic “missing-wedge” problem has presented major challenges in visualization and interpretation of tomograms. Here, we have developed IsoNet, a deep learning-based software package that iteratively reconstructs the missing-wedge information and increases signal-to-noise ratio, using the knowledge learned from raw tomograms. Without the need for sub-tomogram averaging, IsoNet generates tomograms with significantly reduced resolution anisotropy. Applications of IsoNet to three representative types of cryoET data demonstrate greatly improved structural interpretability: resolving lattice defects in immature HIV particles, establishing architecture of the paraflagellar rod in Eukaryotic flagella, and identifying heptagon-containing clathrin cages inside a neuronal synapse of cultured cells. Therefore, by overcoming two fundamental limitations of cryoET, IsoNet enables functional interpretation of cellular tomograms without sub-tomogram averaging. Its application to high-resolution cellular tomograms should also help identify differently oriented complexes of the same kind for sub-tomogram averaging.
Cryogenic electron tomography suffers from anisotropic resolution due to the missing-wedge problem. Here, the authors present IsoNet, a neural network that learn the feature representation from similar structures in the tomogram and recover the missing information for isotropic tomogram reconstruction.
Journal Article
Mesophasic organization of GABAA receptors in hippocampal inhibitory synapses
Information processing in the brain depends on specialized organization of neurotransmitter receptors and scaffolding proteins within the postsynaptic density. However, how these molecules are organized in situ remains largely unknown. In this study, template-free classification of oversampled sub-tomograms was used to analyze cryo-electron tomograms of hippocampal synapses. We identified type-A GABA receptors (GABAARs) in inhibitory synapses and determined their in situ structure at 19-Å resolution. These receptors are organized hierarchically: from GABAAR super-complexes with a preferred inter-receptor distance of 11 nm but variable relative angles, through semi-ordered, two-dimensional receptor networks with reduced Voronoi entropy, to mesophasic assembly with a sharp phase boundary. These assemblies likely form via interactions among postsynaptic scaffolding proteins and receptors and align with putative presynaptic vesicle release sites. Such mesophasic self-organization might allow synapses to achieve a ‘Goldilocks’ state, striking a balance between stability and flexibility and enabling plasticity in information processing.Using cryo-electron tomography to detect individual GABAA receptors in hippocampal synapses, we discovered a hierarchical and mesophasic organization of inhibitory postsynaptic density proteins that enables efficient synaptic transmission.
Journal Article
Electrochemical C–H phosphorylation of arenes in continuous flow suitable for late-stage functionalization
The development of efficient and sustainable methods for carbon-phosphorus bond formation is of great importance due to the wide application of organophosphorus compounds in chemistry, material sciences and biology. Previous C–H phosphorylation reactions under nonelectrochemical or electrochemical conditions require directing groups, transition metal catalysts, or chemical oxidants and suffer from limited scope. Herein we disclose a catalyst- and external oxidant-free, electrochemical C–H phosphorylation reaction of arenes in continuous flow for the synthesis of aryl phosphorus compounds. The C–P bond is formed through the reaction of arenes with anodically generated P-radical cations, a class of reactive intermediates remained unexplored for synthesis despite intensive studies of P-radicals. The high reactivity of the P-radical cations coupled with the mild conditions of the electrosynthesis ensures not only efficient reactions of arenes of diverse electronic properties but also selective late-stage functionalization of complex natural products and bioactive compounds. The synthetic utility of the electrochemical method is further demonstrated by the continuous production of 55.0 grams of one of the phosphonate products.
Synthesis of aryl phosphorus compounds with electron-withdrawing substituents on the arene is difficult to do simply. Here the authors show a method to form aryl carbon-phosphorus bonds through electrochemistry, without requiring any catalyst or external oxidant.
Journal Article
Association of the dietary copper intake with all-cause and cardiovascular mortality: A prospective cohort study
Copper (Cu) is a component that performs a crucial role in the normal function and development of the human body. Nonetheless, it is still largely unclear how Cu consumption in the diet relates to the risk for all-cause and cardiovascular disease (CVD) mortality. Data from the National Health and Nutrition Examination Survey from 2001-2018 were used to conduct a prospective cohort study of individuals between the ages of 20 years and above. Regression coefficients and 95% confidence intervals for the link between dietary Cu consumption and all-cause and cardiovascular-related mortality were computed utilizing univariate and multivariate-adjusted Cox proportional hazards models. A total of 197.9 million non-institutionalized American citizens were represented by the NHANES's 39,784 participants. The link between Cu in the diet and all-cause mortality was discovered to be non-linear in our restricted cubic spline regression models. When comparing the highest with the lowest quartile of Cu consumption in the diet, the weighted multivariate hazard ratios for all-cause mortality were 0.91 (0.83-0.99) for Q2, 0.88 (0.80-0.97) for Q3, and 0.86 (0.76-0.98) for Q4 (P for trend = 0.017). An identical trend was observed for cardiovascular mortality, but the association is not significant. The most important discovery was that higher dietary Cu consumption was associated with a lower risk of all-cause mortality. This trend was also consistent with that of cardiovascular-related mortality, but the association is not significant.
Journal Article
A study of the correlations between IVIM-DWI parameters and the histologic differentiation of hepatocellular carcinoma
The present study aimed to investigate the value of intravoxel incoherent motion diffusion weighted imaging (IVIM-DWI) in the preoperative prediction of the histologic differentiation of hepatocellular carcinoma (HCC). Seventy HCC patients were scanned with a 3.0 T magnetic resonance scanner. The values of apparent diffusion coefficient (ADC), slow apparent diffusion coefficient (D), fast apparent diffusion coefficient (D*), and the fraction of the fast apparent diffusion coefficient (f) were measured. Analysis of variance was used to compare the differences in parameters between groups with different degrees of histologic differentiation.
p
< 0.05 was considered statistically significant. Receiver operating characteristic (ROC) curves were used to analyse the efficacy of IVIM-DWI parameters for predicting the histologic differentiation of HCC. The ADC and D values for well, moderately and poorly differentiated HCC were 1.35 ± 0.17 × 10
−3
mm
2
/s, 1.16 ± 0.17 × 10
−3
mm
2
/s, 0.98 ± 0.21 × 10
−3
mm
2
/s, and 1.06 ± 0.15 × 10
−3
mm
2
/s, 0.88 ± 0.16 × 10
−3
mm
2
/s, 0.76 ± 0.18 × 10
−3
mm
2
/s, respectively, and all differences were significant. The D* and f values of the three groups were 32.87 ± 14.70 × 10
−3
mm
2
/s, 41.68 ± 17.90 × 10
−3
mm
2
/s, 34.54 ± 18.60 × 10
−3
mm
2
/s and 0.22 ± 0.07, 0.23 ± 0.08, 0.18 ± 0.07, respectively, with no significant difference. When the cut-off values of ADC and D were 1.25 × 10
−3
mm
2
/s and 0.97 × 10
−3
mm
2
/s, respectively, their diagnostic sensitivities and specificities for distinguishing well differentiated HCC from moderately differentiated and poorly differentiated HCC were 73.3%, 85.5%, 86.7%, and 78.2%, and their areas under the ROC curve were 0.821 and 0.841, respectively. ADC and D values can be used preoperatively to predict the degree of histologic differentiation in HCC, and the D value has better diagnostic value.
Journal Article
Effects of probiotics on type II diabetes mellitus: a meta-analysis
Objective
The purpose of the present study was to evaluate the effectiveness of probiotics on type II diabetes mellitus (T2DM).
Methods
We performed a comprehensive search on PubMed, Web of Science, China National Knowledge Infrastructure, Chinese Scientific Journal Databases, Wan Fang database and China biology medicine disc for relevant studies published before June 2019. Glycated hemoglobin A1c (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) and fasting blood glucose (FBG) were used as indicators for T2DM. Inverse-variance weighted mean difference (WMD) with 95% confidence interval (CI) was calculated for the mean HbA1c, FBG and HOMA-IR changes from baseline.
Results
15 randomized controlled trials (RCT) with a total of 902 participants were included into the meta-analysis. Considering the clinical heterogeneity caused by variation of dosage and duration of probiotic treatment, random-effects model was used to estimate the pooled WMD. Significantly greater reduction in HbA1c% (WMD = − 0.24, 95% CI [− 0.44, − 0.04],
p
= 0.02), FBG (WMD = − 0.44 mmol/L, 95% CI [− 0.74, − 0.15],
p
= 0.003) and HOMA-IR (WMD = − 1.07, 95% CI [− 1.58, − 0.56],
p
< 0.00001) were observed in probiotics treated group. Further sensitivity analysis verified the reliability and stability of our results.
Conclusion
The results of our meta-analysis indicated that probiotics treatment may reduce HbA1c, FBG and insulin resistance level in T2DM patients. More clinical data and research into the mechanism of probiotics are needed to clarify the role of probiotics in T2DM.
Journal Article
Albumin infusion in hospitalized patients with acute heart failure: a retrospective cohort study
Background
Heart failure is frequently associated with hypoalbuminaemia and poor prognosis. Acute heart failure (AHF) patients are commonly treated with intravenous albumin to improve osmotic pressure and haemodynamics. However, the effects of exogenous albumin supplementation on the fatality rate of AHF patients have not yet been demonstrated. Therefore, the present study strived to examine the impacts of albumin injections on the mortality rate of patients with AHF.
Methods
This retrospective cohort study evaluated the clinical outcomes of all consecutive hospitalized patients. Data were collected from medical records. The primary end-point was a composite of intubation, emergency renal replacement, or mortality in a time-to-event analysis. An inverse probability-weighted multivariable Cox model was used to compare outcomes between patients who were treated with albumin and those who were not based on the propensity score.
Results
Among the 1420 consecutive patients hospitalized in our hospital with acute decompensated heart failure between 1 January 2017 and 27 February 2021, 382 were excluded, 337 (32.5%) were administered albumin (median treatment dose of 29.0 g), and 701 (67.5%) were not. The albumin exposure varied by body mass index, age group, previous diagnoses, clinical signs and symptoms, laboratory tests, and use of other drugs in the unmatched sample. The patients receiving albumin exhibited a lower serum albumin level at baseline in contrast with those who were not treated with albumin (median, 37.3 g/L vs. 31.7 g/L, respectively). Overall, primary end-point events occurred in 357 patients (34.4%) (79 died without being intubated or during an emergency renal replacement therapy, 118 were intubated and 160 had an emergency renal replacement therapy). In the inverse probability weighted multivariable analysis based on the propensity score, albumin use was not significantly associated with the composite primary end-point (hazard ratio, 1.05; 95% confidence interval, 0.75–1.47).
Conclusion
In this observational study of AHF patients hospitalized in our hospital, the administration of albumin did not show a relationship with either a greatly reduced or aggregated risk of the composite end-point of intubation, emergency renal replacement therapy, or death. Therefore, randomized controlled trials of albumin administration are needed for patients with AHF.
Journal Article
Structure of human cytomegalovirus virion reveals host tRNA binding to capsid-associated tegument protein pp150
Under the Baltimore nucleic acid-based virus classification scheme, the herpesvirus human cytomegalovirus (HCMV) is a Class I virus, meaning that it contains a double-stranded DNA genome—and no RNA. Here, we report sub-particle cryoEM reconstructions of HCMV virions at 2.9 Å resolution revealing structures resembling non-coding transfer RNAs (tRNAs) associated with the virion’s capsid-bound tegument protein, pp150. Through deep sequencing, we show that these RNA sequences match human tRNAs, and we built atomic models using the most abundant tRNA species. Based on our models, tRNA recruitment is mediated by the electrostatic interactions between tRNA phosphate groups and the helix-loop-helix motif of HCMV pp150. The specificity of these interactions may explain the absence of such tRNA densities in murine cytomegalovirus and other human herpesviruses.
Here, cryo-EM reconstructions of human cytomegalovirus (HCMV) virions reveal host tRNAs associated with the virion’s capsid-bound tegument protein, pp150. tRNA recruitment is mediated by the interactions specific for HCMV only, suggesting the explanation for the absence of such tRNA densities in related herpesviruses.
Journal Article