Publications by authors named "Wen Han"

175 Publications

Impact of mTOR signaling pathway on CD8+ T cell immunity through Eomesodermin in response to invasive candidiasis.

J Microbiol Immunol Infect 2021 Apr 20. Epub 2021 Apr 20.

Department, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China; Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address:

Background: We investigated the effect of the mammalian target of rapamycin (mTOR) pathway on CD8+ T cell immunity through Eomesodermin (Eomes) in intensive care unit (ICU) patients with invasive candidiasis (IC) and in a mouse model.

Methods: We evaluated quantitative changes in parameters of the mTOR/phosphorylated ribosomal S6 kinase (pS6K) pathway and immune system at the onset of infection in ICU patients. The study was registered on 28 February 2017 at chictr.org.cn (ChiCTR-ROC-17010750). We also used a mouse model of Candida infection and constructed T-cell-specific mTOR and T-cell-specific tuberous sclerosis complex (TSC) 1 conditional knockout mice to elucidate the molecular mechanisms.

Results: We enrolled 88 patients, including 8 with IC. The IC group had lower CD8+ T cell counts, higher serum levels of mTOR, pS6K, Eomes and interleukin (IL)-6. The mouse model with IC showed results consistent in the clinical study. The CD8+ T cell immune response to IC seemed to be weakened in TSC1 knockout mice compared with wild-type IC mice, demonstrating that mTOR activation resulted in the impaired CD8+ T cell immunity in IC.

Conclusions: In IC, the mTOR activation may play a vital role in impaired CD8+ T cell immunity through enhancing expression of Eomes. The study was registered on 28 February 2017 at chictr.org.cn (identifier ChiCTR-ROC-17010750).
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http://dx.doi.org/10.1016/j.jmii.2021.03.021DOI Listing
April 2021

A novel ratiometric and colorimetric chemosensor for highly sensitive, selective and ultrafast tracing of HClO in live cells, bacteria and zebrafish.

Anal Chim Acta 2021 May 5;1161:338472. Epub 2021 Apr 5.

School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address:

Hypochlorous acid (HClO) along with its ionic form, hypochlorite anion (ClO) are critical reactive oxygen species (ROS), which play vital roles in biological systems. Dysregulated production of HClO/ClO can result in tissue damage and cause a variety of diseases. Besides, Sodium hypochlorite has been widely used as a bleaching agent for water disinfection, surface cleaning in daily life. Excessive exposure to sodium hypochlorite will lead to symptoms of severe breathing and skin problems. Therefore, developing a state-of-the-art (simple, highly sensitive, highly selective and super fast-response) sensor for tracking HClO is of biological, toxicological, and environmental importance. Though many HClO probes have been reported so far, this big aim still presents a challenge. Researchers around the world are continuing to develop new HClO probes that could improve their sensitivity, selectivity, the limit of detection, response time, easiness to use, etc. Herein, with coumarin as the fluorophore molecule, we rationally developed a novel chemosensor (CMTH) for detecting HClO with both ratiometric and colorimetric responses resulted from the oxidation reaction of CN bond. Further analysis results indicated that CMTH can realize highly sensitive with low limit of detection (256 nM, among the best of its kind) and highly selective (over a bunch of interfering analytes) imaging detection of HClO in multiple organisms with low cytotoxicity, and good cell and tissue permeability as well. In particular, compared to other fluorescent HClO probes reported so far, CMTH excels in the response time to HClO (< 40 s), being the top-notch of its kind. Besides, owing to its excellent water solubility, CMTH can also be applied to track HClO in the environmental system. Taken together, we have presented here a novel chemosensor, CMTH, as a colorimetric and ratiometric chemosensor for highly sensitive and ultrafast imaging detection of HClO in aqueous solutions, eukaryotic cells, prokaryotic bacteria and vertebrate zebrafish.
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http://dx.doi.org/10.1016/j.aca.2021.338472DOI Listing
May 2021

Reaction-based chemosensor as dual-channel indicator for visualizing and bioimaging of exogenous hypochlorite concentrations in living cells, Pseudomonas aeruginosa, and zebrafish.

Anal Chim Acta 2021 May 12;1157:338391. Epub 2021 Mar 12.

School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China; Engineering Research Center of Clinical Functional Materials and Diagnosis & Treatment Devices of Zhejiang Province, Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou, Zhejiang, 325001, China. Electronic address:

Tracking and quantifying hypochlorite (ClO) in biological systems and environments remain challenging tasks, and many efforts have been made to improve ClO recognition performance by modifying the sensor structure. In this study, a pre-designed coumarin/furanohydrazide-based sensor (CMFH) with the coumarin moiety as the building block (fluorogen) was rationally prepared as a ratiometric and colorimetric chemosensor for ClO recognition. As expected, CMFH demonstrated excellent sensitivity and selectivity for ClO detection. The fluorescence signal ratio (F/F) showed strong ClO dependency, and the sensor exhibited ultrafast detection (within 60 s) and a low detection limit of 563 nM. Due to its low cytotoxicity and good tissue permeability, CMFH was demonstrated as a dual-channel sensor for ClO bioimaging and visualization in cells, zebrafish, and even bacteria. Furthermore, CMFH-loaded paper strips were successfully applied to the colorimetric and fluorescent visualization of ClO. The results demonstrate that CMFH has potential application value for tracking ClO in various biosystems and environments.
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http://dx.doi.org/10.1016/j.aca.2021.338391DOI Listing
May 2021

Association between age-related kidney function and vascular subclinical state in a healthy Chinese population.

Chin Med J (Engl) 2021 Mar 31. Epub 2021 Mar 31.

Department of Gerontology and Geriatrics, Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong 519099, China Department of Gerontology and Geriatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China Department of Kidney, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.

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http://dx.doi.org/10.1097/CM9.0000000000001422DOI Listing
March 2021

Multifocal Calcific Periarthritis with Distinctive Clinical and Radiological Features in Patients with CD73 Deficiency.

Rheumatology (Oxford) 2021 03 21. Epub 2021 Mar 21.

National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.

Objective: Arterial calcification due to deficiency of CD73 (ACDC) is a hereditary autosomal recessive ectopic mineralization syndrome caused by loss-of-function mutations in the 5'-nucleotidase Ecto (NT5E) gene. Periarticular calcification has been reported but the clinical characterization of arthritis as well as the microstructure and chemical composition of periarticular calcifications and synovial fluid crystals has not been systematically investigated.

Methods: Eight ACDC patients underwent extensive rheumatological and radiological evaluation over a period of 11 years. Periarticular and synovial biopsies were obtained from four patients. Characterization of crystal composition was evaluated by compensated polarized light microscopy, Alizarin red staining for synovial fluid along with x-ray diffraction and x-ray micro tomosynthesis for periarticular calcification.

Results: Arthritis in ACDC patients has a clinical presentation of mixed erosive-degenerative joint changes with a median onset of articular symptoms at 17 years of age and progresses over time to the development of fixed deformities and functional limitations of small peripheral joints with eventually, larger joint and distinct axial involvement later in life. We have identified calcium pyrophosphate (CPP) and calcium hydroxyapatite (CHA) crystals in synovial fluid specimens and determined that CHA crystals are the principal component of periarticular calcifications.

Conclusion: This is the largest study in ACDC patients to describe erosive peripheral arthropathy and axial enthesopathic calcifications over a period of 11 years and the first to identify the composition of periarticular calcifications and synovial fluid crystals. ACDC should be considered among the genetic causes of early-onset osteoarthritis, as musculoskeletal disease signs may often precede vascular symptoms.
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http://dx.doi.org/10.1093/rheumatology/keab270DOI Listing
March 2021

Predicting lipid and ligand binding sites in TRPV1 channel by molecular dynamics simulation and machine learning.

Proteins 2021 Mar 19. Epub 2021 Mar 19.

Department of Physics, State University of New York at Buffalo, Buffalo, New York, USA.

As a key cellular sensor, the TRPV1 channel undergoes a gating transition from a closed state to an open state in response to many physical and chemical stimuli. This transition is regulated by small-molecule ligands including lipids and various agonists/antagonists, but the underlying molecular mechanisms remain obscure. Thanks to recent revolution in cryo-electron microscopy, a growing list of new structures of TRPV1 and other TRPV channels have been solved in complex with various ligands including lipids. Toward elucidating how ligand binding correlates with TRPV1 gating, we have performed extensive molecular dynamics simulations (with cumulative time of 20 μs), starting from high-resolution structures of TRPV1 in both the closed and open states. By comparing between the open and closed state ensembles, we have identified state-dependent binding sites for small-molecule ligands in general and lipids in particular. We further use machine learning to predict top ligand-binding sites as important features to classify the closed vs open states. The predicted binding sites are thoroughly validated by matching homologous sites in all structures of TRPV channels bound to lipids and other ligands, and with previous functional/mutational studies of ligand binding in TRPV1. Taken together, this study has integrated rich structural, dynamic, and functional data to inform future design of small-molecular drugs targeting TRPV1.
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http://dx.doi.org/10.1002/prot.26075DOI Listing
March 2021

A yeast-based drug discovery platform to identify type II NADH dehydrogenase inhibitors.

Antimicrob Agents Chemother 2021 Mar 15. Epub 2021 Mar 15.

State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.

Conventional methods utilizing protein activity assay or parasite survival to screen for malaria inhibitors suffer from high experimental background and/or inconvenience. Here we introduce a yeast-based system to facilitate chemical screen for specific protein or pathway inhibitors. The platform comprises several isogeneic strains that only differ in the target of interest, so that a compound which inhibits one strain but not the other is implicated in working specifically against the target. We used NDH2(PfNDH2), a type II NADH dehydrogenase, as a proof of principle to show how well this works. Three isogenic strains harboring respectively exogeneously introduced PfNDH2, its own complex I (a type I NADH dehydrogenase), and PfNDH2 with its own complex I were constructed. In a pilot screen of more than2000 compounds, we identified a highly specific inhibitor that acts on PfNDH2. This compound poorly inhibit the parasites at the asexual blood stage, however, is highly effective in repressing oocyst maturation in the mosquito stage. Our results demonstrate that the yeast cell based screen platform is feasible, efficient, economical and with very low background noise. Similar strategies could be extended to the functional screen for interacting molecules of other targets.
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http://dx.doi.org/10.1128/AAC.02470-20DOI Listing
March 2021

Rational design of a prodrug to inhibit self-inflammation for cancer treatment.

Nanoscale 2021 Mar 12;13(11):5817-5825. Epub 2021 Mar 12.

MOE Key Laboratory for Analytical Science of Food Safety and Biology; Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety; State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry, Fuzhou, Fujian 350116, P. R. China.

Photothermal therapy (PTT) has been extensively used as an effective therapeutic approach against cancer. However, PTT can trigger the proinflammatory response of dendritic cells (DCs) and macrophages to release proinflammatory cytokines, which can simulate tumor regeneration and further hinder subsequent therapy. Hence, an effective therapeutic system, comprising gold nanoparticle modified CuZnSnS nanocrystals and aspirin (Au-CZTS/Asp), was developed to co-deliver PTT agents and inflammatory inhibitors for the synergistic treatment of cancer. Au-CZTS with high near infrared (NIR) photothermal conversion abilities can effectively induce apoptosis and tumor ablation under NIR light. Furthermore, Asp can inhibit the activation of the cGAS-STING pathway in DCs and the polarization of macrophages to intercept the PTT mediated inflammatory responses. Therefore, the as-prepared Au-CZTS/Asp can effectively realize the integration of tumor treatment and recovery. Simultaneously, the Au-CZTS/Asp with ultrasmall size can be rapidly cleared to reduce biotoxicity and side effects. In addition, the Au-CZTS/Asp showed excellent photoacoustic (PA) imaging properties around the tumor in vivo. Thus, our study provides a potential platform for a nano-prodrug that is viable for cancer diagnostic-treatment-recovery integration.
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http://dx.doi.org/10.1039/d1nr00132aDOI Listing
March 2021

Benign monomelic amyotrophy of lower limb in a cohort of chinese patients.

Brain Behav 2021 Apr 2;11(4):e02073. Epub 2021 Mar 2.

Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Background: Benign monomelic amyotrophy of lower limb (BMALL) is a neurogenic syndrome representing an unclear field. Further studies might be helpful to elucidate uncertainties regarding causation, outcome, and the risk of progression to amyotrophic lateral sclerosis (ALS).

Methods: According to the inclusion and exclusion criteria, 37 patients with BMALL were retrospectively collected in three neuromuscular centers from January 2012 to October 2018. The detailed medical data were summarized. Multiple laboratory tests were examined. Routine electrophysiological examinations, muscle MRI of lower limbs, and muscle biopsy were conducted.

Results: The cohort included 24 male and 13 female cases with median age of onset 47 years. Muscle MRI revealed that the distribution of involved muscles matched with the extent of fat infiltration, so the pattern muscle atrophy can be divided into the following four types: six patients with thigh atrophy (type I), 14 patients with leg atrophy (type II); 10 patients with disproportionate atrophy in both thigh and leg (type III); and seven patients with well-proportionate atrophy in both thigh and leg (type IV). Electrophysiological findings showed neurogenic pattern, spontaneous activity, and abnormal H reflex, which suggested a disorder of spinal anterior horn cell in the patients with types I-III. However, no electrophysiological abnormalities were found in the patients with type IV. Muscle pathology varied from almost normal pattern to advanced neurogenic pattern in nine biopsied patients. Follow-up showed that two patients with type II developed to ALS four years later, and all patients with type IV were in stable condition without any complaints.

Conclusion: Muscle MRI was useful to exactly localize the distribution of involved muscles in BMALL patients. The distribution of atrophic muscles can be roughly divided into four types based on the MRI features. The classification of distributing types might be as an indicator for the prognosis of BMALL.
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http://dx.doi.org/10.1002/brb3.2073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035448PMC
April 2021

Rapamycin inhibits pathogen transmission in mosquitoes by promoting immune activation.

PLoS Pathog 2021 Feb 24;17(2):e1009353. Epub 2021 Feb 24.

The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.

Repeated blood meals provide essential nutrients for mosquito egg development and routes for pathogen transmission. The target of rapamycin, the TOR pathway, is essential for vitellogenesis. However, its influence on pathogen transmission remains to be elucidated. Here, we show that rapamycin, an inhibitor of the TOR pathway, effectively suppresses Plasmodium berghei infection in Anopheles stephensi. An. stephensi injected with rapamycin or feeding on rapamycin-treated mice showed increased resistance to P. berghei infection. Exposing An. stephensi to a rapamycin-coated surface not only decreased the numbers of both oocysts and sporozoites but also impaired mosquito survival and fecundity. Transcriptome analysis revealed that the inhibitory effect of rapamycin on parasite infection was through the enhanced activation of immune responses, especially the NF-κB transcription factor REL2, a regulator of the immune pathway and complement system. Knockdown of REL2 in rapamycin-treated mosquitoes abrogated the induction of the complement-like proteins TEP1 and SPCLIP1 and abolished rapamycin-mediated refractoriness to Plasmodium infection. Together, these findings demonstrate a key role of the TOR pathway in regulating mosquito immune responses, thereby influencing vector competence.
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http://dx.doi.org/10.1371/journal.ppat.1009353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939355PMC
February 2021

Anti-NSCLC activity in vitro of Hsp90 inhibitor KW-2478 and complex crystal structure determination of Hsp90-KW-2478.

J Struct Biol 2021 Feb 19;213(2):107710. Epub 2021 Feb 19.

Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic & Translational Medicine, Xi'an Medical University, Xi'an 710021, China. Electronic address:

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90  (Hsp90). Absence of complex crystal structure of Hsp90-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, K, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC, 8.16 μM for A549; 14.29 μM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90 evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.
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http://dx.doi.org/10.1016/j.jsb.2021.107710DOI Listing
February 2021

Ultra-Small Lung Cysts Impair Diffusion Without Obstructing Air Flow in Lymphangioleiomyomatosis.

Chest 2021 Feb 5. Epub 2021 Feb 5.

National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Electronic address:

Background: Lymphangioleiomyomatosis (LAM) is a rare lung disease found primarily in women of childbearing age, characterized by the formation of air-filled cysts, which may be associated with reductions in lung function. An experimental, regional ultra-high resolution CT scan identified an additional volume of cysts relative to standard chest CT imaging, which consisted primarily of ultra-small cysts.

Research Question: What is the impact of these ultra-small cysts on the pulmonary function of patients with LAM?

Study Design And Methods: A group of 103 patients with LAM received pulmonary function tests and a CT examination in the same visit. Cyst score, the percentage lung volume occupied by cysts, was measured by using commercial software approved by the US Food and Drug Administration. The association between cyst scores and pulmonary function tests of diffusing capacity of the lungs for carbon monoxide (Dlco) (% predicted), FEV (% predicted), and FEV/FVC (% predicted) was assessed with statistical analysis adjusted for demographic variables. The distributions of average cyst size and ultra-small cyst fraction among the patients were evaluated.

Results: The additional cyst volume identified by the experimental, higher resolution scan consisted of cysts of 2.2 ± 0.8 mm diameter on average and are thus labeled the "ultra-small cyst fraction." It accounted for 27.9 ± 19.0% of the total cyst volume among the patients. The resulting adjusted, whole-lung cyst scores better explained the variance of Dlco (P < .001 adjusted for multiple comparisons) but not FEV and FEV/FVC (P ≈ 1.000). The ultra-small cyst fraction contributed to the reduction in Dlco (P < .001) but not to FEV and FEV/FVC (P = .760 and .575, respectively). The ultra-small cyst fraction and average cyst size were correlated with cyst burden, FEV, and FEV/FVC but less with Dlco.

Interpretation: The ultra-small cysts primarily contributed to the reduction in Dlco, with minimal effects on FEV and FEV/FVC. Patients with lower cyst burden and better FEV and FEV/FVC tended to have smaller average cyst size and higher ultra-small cyst fraction.

Clinical Trial Registration: ClinicalTrials.gov; No.: NCT00001465; URL: www.clinicaltrials.govclinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.01.077DOI Listing
February 2021

Effect of Nurse-Led Goal-Directed Lung Physical Therapy on the Prognosis of Pneumonia in Sepsis Patients in the ICU: A Prospective Cohort Study.

J Intensive Care Med 2021 Jan 29:885066620987200. Epub 2021 Jan 29.

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing, China.

Background: Pneumonia poses a significant burden on healthcare systems. However, few studies have focused on nurse-led goal-directed lung physical therapy (GDLPT) for pneumonia in sepsis patients in the intensive care unit (ICU).

Objectives: This study aimed to investigate the effects of nurse-led GDLPT on the prognosis of pneumonia in sepsis patients in the ICU.

Methods: We performed a prospective 2-phase (before-and-after) study over 3 years. After an observational phase (phase 1, = 188), we designed, implemented, and evaluated a nurse-led GDLPT protocol (phase 2, = 359) for pneumonia in sepsis patients in the ICU. The primary outcome was 28-day mortality.

Results: We evaluated 742 critically ill patients with sepsis from January 2017 to January 2020. Among the 742 sepsis patients, 609 were diagnosed with pneumonia and 547 who met the inclusion criteria were enrolled in the study. Compared with patients in phase 1, patients in phase 2 had significantly shorter mechanical ventilation duration (5 [4, 6] days vs. 5 [4, 8] days, = 0.037), shorter ICU stay (9 [4, 16] days vs. 9 [6, 20] days, = 0.010), lower ICU mortality (15.0% [54/359] vs. 25.5% [48/188], = 0.003), and lower 28-day mortality (16.7% [60/359] vs. 27.1% ([51/188], = 0.004). Multivariate logistic regression analysis revealed that nurse-led GDLPT (odds ratio 0.540, 95% confidence interval 0.345-0.846, = 0.007), clinical pulmonary infection score (odds ratio 1.111, 95% confidence interval 1.012-1.221, = 0.028), and ventilation day (OR 1.160, 95% CI, 1.058-1.240, <0.001)were independent predictors of 28-day mortality for pneumonia in sepsis patients, and that nurse-led GDLPT was a protective factor.

Conclusions: Nurse-led GDLPT improved the outcomes of pneumonia in sepsis patients, and was particularly associated with shortened mechanical ventilation duration and ICU stay, and reduced ICU mortality and 28-day mortality.
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http://dx.doi.org/10.1177/0885066620987200DOI Listing
January 2021

X-ray microtomosynthesis of unstained pathology tissue samples.

J Microsc 2021 Jan 22. Epub 2021 Jan 22.

National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.

In pathology protocols, a tissue block, such as one containing a mouse brain or a biopsy sample from a patient, can produce several hundred thin sections. Substantial time may be required to analyse all sections. In cases of uncertainty regarding which sections to focus on, noninvasive scout imaging of intact blocks can help in guiding the pathology procedure. The scouting step is ideally done in a time window of minutes without special sample preparation that may interfere with the pathology procedures. The challenge is to obtain some visibility of unstained tissue structures at sub-10 µm resolution. We explored a novel x-ray tomosynthesis method as a way to maximise contrast-to-noise ratio, a determinant of tissue visibility. It provided a z-stack of thousands of images at 7.3 μm resolution (10% contrast, half-period of 68.5 line pairs/mm), in scans of 5-15 minutes. When compared with micro-CT scans, the straight-line tomosynthesis scan did not need to rotate the sample, which allowed flat samples, such as paraffin blocks, to be kept as close as possible to the x-ray source. Thus, given the same hardware, scan time and resolution, this mode maximised the photon flux density through the sample, which helped in maximising the contrast-to-noise ratio. The tradeoff of tomosynthesis is incomplete 3D information. The microtomosynthesis scanner has scanned 110 unstained human and animal tissue samples as part of their respective pathology protocols. In all cases, the z-stack of images showed tissue structures that guided sectioning or provided correlative structural information. We describe six examples that presented different levels of visibility of soft tissue structures. Additionally, in a set of coronary artery samples from an HIV patient donor, microtomosynthesis made a new discovery of isolated focal calcification in the internal elastic lamina of coronary wall, which was the onset of medial calcific sclerosis in the arteries.
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http://dx.doi.org/10.1111/jmi.13003DOI Listing
January 2021

Cross-subunit interactions that stabilize open states mediate gating in NMDA receptors.

Proc Natl Acad Sci U S A 2021 01;118(2)

Department of Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY 14203;

NMDA receptors are excitatory channels with critical functions in the physiology of central synapses. Their activation reaction proceeds as a series of kinetically distinguishable, reversible steps, whose structural bases are currently under investigation. Very likely, the earliest steps include glutamate binding to glycine-bound receptors and subsequent constriction of the ligand-binding domain. Later, three short linkers transduce this movement to open the gate by mechanical pulling on transmembrane helices. Here, we used molecular and kinetic simulations and double-mutant cycle analyses to show that a direct chemical interaction between GluN1-I642 (on M3 helix) and GluN2A-L550 (on L1-M1 linker) stabilizes receptors after they have opened and thus represents one of the structural changes that occur late in the activation reaction. This native interaction extends the current decay, and its absence causes deficits in charge transfer by GluN1-I642L, a pathogenic human variant.
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http://dx.doi.org/10.1073/pnas.2007511118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812756PMC
January 2021

An evolutionary life history approach to understanding mental health.

Gen Psychiatr 2020 1;33(6):e100113. Epub 2020 Oct 1.

Department of Psychology, Fudan University, Shanghai, China.

In recent years, evolutionary life history theory has been used as a heuristic framework to understand mental health. This article reviews the life history theory and its integration with mental disorders and then introduces representative research methods and related empirical studies in the field of evolutionary psychopathology. In the end, this article concludes with future directions for further research examining and developing the evolutionary psychopathological framework.
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http://dx.doi.org/10.1136/gpsych-2019-100113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534052PMC
October 2020

Evaluation of the updated " score" with Sepsis 3.0 criteria in critically ill patients.

Ann Transl Med 2020 Aug;8(15):917

Department of Critical Care Medicine, Peking Union Medical College Hospital, Beijing, China.

Background: The score proposed in 2009 was calculated on the definition of "severe sepsis", which was removed in the Sepsis 3.0 definition. This study investigated the clinical relevance of score with the updated Sepsis 3.0 definition (CS-3.0) instead of severe sepsis (CS-2009) in the new admitted critically ill patients.

Methods: We performed a retrospective analysis on a single center public database. All patients with ICU stay ≥72 hours were included in this study. The score was calculated based on the data collected on ICU admission. The incidence of invasive candidiasis was determined and its relationship with the CS-2009 and CS-3.0 was studied.

Results: A total of 17,666 patients were identified after screening 58,976 hospital admissions, and 436 cases (2.5%) were diagnosed with invasive candidiasis. In the infection group, the number of patients who met the Sepsis 3.0 criteria was greater than the number of patients with severe sepsis (81.2% 78.4%, P<0.005). The area under curve of the CS-2009 was 0.789 (95% CI: 0.765-0.813) and the CS-3.0 was 0.804 (95% CI: 0.782-0.827).

Conclusions: Our study confirmed the clinical relevance and comparative superiority of the updated score model, using the Sepsis 3.0 definition, compared with the classic sepsis/severe sepsis model, in assessment of critically ill patients. Considering the clinical importance of organ dysfunction in ICI, the Sepsis 3.0 should be used as the basis for prediction of invasive candidiasis.
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http://dx.doi.org/10.21037/atm-20-995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475415PMC
August 2020

Morphology and chemical identity of periarticular and vascular calcification in a patient with the rare genetic disease of arterial calcification due to deficiency of CD73 (ACDC).

Radiol Case Rep 2020 Oct 14;15(10):1883-1886. Epub 2020 Aug 14.

National Heart, Lung, and Blood Institute, National Institutes of Health; 9000 Rockville Pike, Bethesda, MD 20892 USA.

A 54-year old female patient with the genetic disease of arterial calcification due to deficiency of CD73 was studied under the Undiagnosed Disease Program of the National Institutes of Health. She presented with symptoms of claudication in her 40s and later developed arthritic symptoms, ectopic calcification in her left hand and severe arterial calcifications of the lower extremities. Since little was known about the composition of the calcifications in arterial calcification due to deficiency of CD73, we investigated their chemical identity and microscopic morphology in this patient with imaging and x-ray diffraction analysis. We found that, microscopically, the bulk calcifications consisted of fragments of either solid or porous internal structure. Both periarticular and arterial calcifications were primarily hydroxyapatite crystals of the same crystalline anisotropy, but different crystalline grain sizes. This was consistent with the presence of hydroxyapatite crystals along with birefringent calcium pyrophosphate dihydrate crystals in the synovial fluid of the patients by polarized light microscopy. The result suggests that tissue calcification in both locations follow a similar biochemical mechanism caused by an increase in extracellular tissue-nonspecific alkaline phosphatase activity.
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http://dx.doi.org/10.1016/j.radcr.2020.07.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452020PMC
October 2020

Cervical spine osteoradionecrosis or bone metastasis after radiotherapy for nasopharyngeal carcinoma? The MRI-based radiomics for characterization.

BMC Med Imaging 2020 09 1;20(1):104. Epub 2020 Sep 1.

Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.

Background: To develop and validate an MRI-based radiomics nomogram for differentiation of cervical spine ORN from metastasis after radiotherapy (RT) in nasopharyngeal carcinoma (NPC).

Methods: A radiomics nomogram was developed in a training set that comprised 46 NPC patients after RT with 95 cervical spine lesions (ORN, n = 51; metastasis, n = 44), and data were gathered from January 2008 to December 2012. 279 radiomics features were extracted from the axial contrast-enhanced T1-weighted image (CE-T1WI). A radiomics signature was created by using the least absolute shrinkage and selection operator (LASSO) algorithm. A nomogram model was developed based on the radiomics scores. The performance of the nomogram was determined in terms of its discrimination, calibration, and clinical utility. An independent validation set contained 25 consecutive patients with 47 lesions (ORN, n = 25; metastasis, n = 22) from January 2013 to December 2015.

Results: The radiomics signature that comprised eight selected features was significantly associated with the differentiation of cervical spine ORN and metastasis. The nomogram model demonstrated good calibration and discrimination in the training set [AUC, 0.725; 95% confidence interval (CI), 0.622-0.828] and the validation set (AUC, 0.720; 95% CI, 0.573-0.867). The decision curve analysis indicated that the radiomics nomogram was clinically useful.

Conclusions: MRI-based radiomics nomogram shows potential value to differentiate cervical spine ORN from metastasis after RT in NPC.
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http://dx.doi.org/10.1186/s12880-020-00502-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466527PMC
September 2020

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress.

Theranostics 2020 23;10(20):9280-9302. Epub 2020 Jul 23.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou 325000, China.

Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.
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http://dx.doi.org/10.7150/thno.46566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415792PMC
July 2020

Elevating sestrin2 attenuates endoplasmic reticulum stress and improves functional recovery through autophagy activation after spinal cord injury.

Cell Biol Toxicol 2020 Aug 1. Epub 2020 Aug 1.

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.

Spinal cord injury (SCI) is a devastating neurological trauma that causes losses of motor and sensory function. Sestrin2, also known as hypoxia inducible gene 95, is emerging as a critical determinant of cell homeostasis in response to cellular stress. However, the role of sestrin2 in the neuronal response to endoplasmic reticulum (ER) stress and the potential mechanism remain undefined. In this study, we investigated the effects of sestrin2 on ER stress and delineated an underlying molecular mechanism after SCI. Here, we found that elevated sestrin2 is a protective process in neurons against chemical ER stress induced by tunicamycin (TM) or traumatic invasion, while treatment with PERK inhibitor or knockdown of ATF4 reduces sestrin2 expression upon ER stress. In addition, we demonstrated that overexpression of sestrin2 limits ER stress, promoting neuronal survival and improving functional recovery after SCI, which is associated with activation of autophagy and restoration of autophagic flux mediated by sestrin2. Moreover, we also found that sestrin2 activates autophagy dependent on the AMPK-mTOR signaling pathway. Consistently, inhibition of AMPK abrogates the effect of sestrin2 on the activation of autophagy, and blockage of autophagic flux abolishes the effect of sestrin2 on limiting ER stress and neural death. Together, our data reveal that upregulation of sestrin2 is an important resistance mechanism of neurons to ER stress and the potential role of sestrin2 as a therapeutic target for SCI. Graphical abstract.
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http://dx.doi.org/10.1007/s10565-020-09550-4DOI Listing
August 2020

Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel.

Nat Commun 2020 07 29;11(1):3790. Epub 2020 Jul 29.

Department of Biophysics, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, Zhejiang Province, China.

Menthol in mints elicits coolness sensation by selectively activating TRPM8 channel. Although structures of TRPM8 were determined in the apo and liganded states, the menthol-bounded state is unresolved. To understand how menthol activates the channel, we docked menthol to the channel and systematically validated our menthol binding models with thermodynamic mutant cycle analysis. We observed that menthol uses its hydroxyl group as a hand to specifically grab with R842, and its isopropyl group as legs to stand on I846 and L843. By imaging with fluorescent unnatural amino acid, we found that menthol binding induces wide-spread conformational rearrangements within the transmembrane domains. By Φ analysis based on single-channel recordings, we observed a temporal sequence of conformational changes in the S6 bundle crossing and the selectivity filter leading to channel activation. Therefore, our study suggested a 'grab and stand' mechanism of menthol binding and how menthol activates TRPM8 at the atomic level.
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http://dx.doi.org/10.1038/s41467-020-17582-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391767PMC
July 2020

Sitagliptin improves functional recovery via GLP-1R-induced anti-apoptosis and facilitation of axonal regeneration after spinal cord injury.

J Cell Mol Med 2020 08 22;24(15):8687-8702. Epub 2020 Jun 22.

Molecular Pharmacology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, China.

Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP4), resulting in blocking of GLP-1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP-1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP-1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9-39, a GLP-1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC-1α signalling pathway was activated by sitagliptin stimulating GLP-1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP-1R-induced AMPK/ PGC-1α signalling pathway after SCI.
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http://dx.doi.org/10.1111/jcmm.15501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412681PMC
August 2020

Investigating dual Ca modulation of the ryanodine receptor 1 by molecular dynamics simulation.

Proteins 2020 11 13;88(11):1528-1539. Epub 2020 Jul 13.

Department of Physics, University at Buffalo, Buffalo, New York, USA.

The ryanodine receptors (RyR) are essential to calcium signaling in striated muscles. A deep understanding of the complex Ca -activation/inhibition mechanism of RyRs requires detailed structural and dynamic information for RyRs in different functional states (eg, with Ca bound to activating or inhibitory sites). Recently, high-resolution structures of the RyR isoform 1 (RyR1) were solved by cryo-electron microscopy, revealing the location of a Ca binding site for activation. Toward elucidating the Ca -modulation mechanism of RyR1, we performed extensive molecular dynamics simulation of the core RyR1 structure in the presence and absence of activating and solvent Ca (total simulation time is >5 μs). In the presence of solvent Ca , Ca binding to the activating site enhanced dynamics of RyR1 with higher inter-subunit flexibility, asymmetric inter-subunit motions, outward domain motions and partial pore dilation, which may prime RyR1 for subsequent channel opening. In contrast, the solvent Ca alone reduced dynamics of RyR1 and led to inward domain motions and pore contraction, which may cause inhibition. Combining our simulation with the map of disease mutation sites in RyR1, we constructed a wiring diagram of key domains coupled via specific hydrogen bonds involving the mutation sites, some of which were modulated by Ca binding. The structural and dynamic information gained from this study will inform future mutational and functional studies of RyR1 activation and inhibition by Ca .
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http://dx.doi.org/10.1002/prot.25971DOI Listing
November 2020

Natural indole-containing alkaloids and their antibacterial activities.

Arch Pharm (Weinheim) 2020 Oct 18;353(10):e2000120. Epub 2020 Jun 18.

The Second Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, China.

As the growth in resistance to bacterial infection treatments poses a grave threat to global health in the 21st century, there is a constant need to explore novel antibacterial agents that have the ability to overcome drug resistance. Indole-containing alkaloids are widely distributed in nature, and a variety of indole-containing alkaloids have already been applied in clinical practice, proving that indole-containing alkaloids are fascinating and privileged scaffolds for the development of novel drugs. Moreover, indole-containing alkaloids could exert their antibacterial activity through the inhibition of efflux pumps, the biofilm, filamentous temperature-sensitive protein Z, and methicillin-resistant Staphylococcus aureus pyruvate kinase; so, indole-containing alkaloids constitute an important source of novel antibacterial agents. This review is an endeavor to highlight the advances in the development of indole-containing alkaloids with antibacterial potential, covering articles published in the recent 10 years.
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http://dx.doi.org/10.1002/ardp.202000120DOI Listing
October 2020

T-Bet Expression Mediated by the mTOR Pathway Influences CD4 T Cell Count in Mice With Lethal Sepsis.

Front Microbiol 2020 5;11:835. Epub 2020 May 5.

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

The sustained high morbidity and mortality of sepsis are mainly caused by compromise of host immunity. Clinically, it is often manifested as a significant decrease in CD4 T cell count, although the mechanism is unclear. We established a lethal mice sepsis model and used Murine Sepsis Score to group mice with different disease severity to establish the influence of T-bet expression on CD4 T cell count in sepsis. We found that CD4 T cell count decreased in -infected compared to uninfected mice, and the degree of decrease increased with aggravation of sepsis. Expression of T-bet similarly decreased with worsening of sepsis, but it was significantly enhanced in candidiasis in comparison of naïve state. To clarify its possible mechanism, we measured the activity of mammalian target of rapamycin (mTOR), which is a key regulator of T-bet expression. The mTOR pathway was activated after infection and its activity increased with progression of sepsis. We used mice with T-cell-specific knockout of or tuberous sclerosis complex ()1 to further inhibit or strengthen the mTOR signaling pathway. We found that deletion mice had a higher CD4 T cell count by regulating T-bet expression, and the result in deletion mice was reversed. These results demonstrate that T-bet expression mediated by the mTOR pathway influences the CD4 T cell count in mice with sepsis.
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http://dx.doi.org/10.3389/fmicb.2020.00835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214724PMC
May 2020

Association of cathepsin B and cystatin C with an age-related pulmonary subclinical state in a healthy Chinese population.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620921751

Department of Gerontology and Geriatrics, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China.

Background: Cathepsin B (CTSB) and cystatin C (CYSC) are new biomarkers for several physiological and pathological processes as their activities increase with age. The aim of this study was to explore population-level associations between serum CTSB and CYSC with an age-related pulmonary subclinical state.

Methods: We examined 401 healthy participants (aged 36-87 years, of which 44.3% were male) in northern Chinese cities. We used a standard spirometer to determine lung function. Serum CTSB and CYSC levels were measured by enzyme-linked immunosorbent assay (ELISA).

Results: For all participants, serum CTSB was related to maximum vital capacity (VC MAX), forced vital capacity (FVC), forced expiratory volume in 1 s, peak expiratory flow, forced expiratory flow at 25% of FVC, forced expiratory volume in 3 s (FEV3), and inspiratory vital capacity (VC IN). These associations were lost after full adjustment. CYSC remained significantly associated with inspiratory capacity (IC), breath frequency (BF;  < 0.001), minute ventilation (MV), the ratio of FEV3 and FVC (FEV3%FVC), and expiratory reserve volume ( < 0.05) after adjusting for all other possible confounders. In males, serum CYSC levels exhibited significant and independent associations with FVC, FEV3 ( < 0.05), and IC ( < 0.001) and serum CTSB levels exhibited significant and independent associations with BF ( < 0.05).

Conclusions: Our results confirmed serum CYSC concentration associations with an age-related lung function in healthy people. However, the association between serum CTSB and lung function was not well confirmed. Serum measurements of CYSC may provide valuable predictors of pulmonary function in healthy people, especially healthy elderly adults. .
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http://dx.doi.org/10.1177/1753466620921751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223214PMC
May 2020

Lymphocyte subset counts as diagnostic and prognostic markers for carbapenem-resistant Enterobacteriaceae (CRE) infection in critically ill patients.

Int J Infect Dis 2020 Jul 7;96:315-322. Epub 2020 May 7.

Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100730, China. Electronic address:

Objectives: This study investigated the use of lymphocyte subset counts as diagnostic and prognostic markers for carbapenem-resistant Enterobacteriaceae (CRE) infection.

Methods: We assessed the lymphocyte subset populations and other clinical parameters of septic patients upon intensive care unit (ICU) admission, and evaluated their potential impact on CRE infection diagnosis and outcome.

Results: Among 373 septic patients, 51 were diagnosed with CRE infection. The 28-day mortality was significantly higher in CRE than non-CRE patients (35.3% vs 14.9%). The T lymphocyte count and CD4CD28 T cell count were both independent risk factors for CRE infection, with the latter had the best diagnostic ability (AUC: 0.908; p < 0.0001). Lower CD4CD28 T cell counts were associated with higher likelihoods of CRE infection. The CRE incidence and 28-day mortality of CRE-infected patients could be predicted using cutoff values of 242 (sensitivity: 83.9%; specificity: 87.5%) and 58.5 (sensitivity: 100%; specificity: 61.1%) CD4CD28 T cells/μl at ICU admission, respectively.

Conclusions: Septic patients with CRE infection had higher 28-day mortality. Given that the CD4CD28 T cell count was significantly lower in CRE than non-CRE septic patients and a lower cell count was significantly associated with higher 28-day mortality, CD4CD28 T cell counts may be useful markers for early diagnosis of CRE infection and outcome prediction.
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http://dx.doi.org/10.1016/j.ijid.2020.04.072DOI Listing
July 2020

FUS P525L mutation causing amyotrophic lateral sclerosis and movement disorders.

Brain Behav 2020 06 19;10(6):e01625. Epub 2020 Apr 19.

Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, China.

Background: Mutations in the fused in sarcoma (FUS) gene have been associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor. Among the FUS mutations, p.P525L as a hot spot variant has been reported in more than 20 patients with ALS. Apart from the typical ALS phenotype, patients with p.P525L mutation exhibit some atypical symptoms. However, movement disorders related to p.P525L mutation have not been emphasized currently.

Methods: Two unrelated patients with ALS were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through next-generation sequencing. Muscle biopsies were performed on the 2 patients. Muscle samples were stained according to standard histological and immunohistochemical procedures.

Results: The first patient presented with juvenile-onset neurogenic weakness and wasting and simultaneously had dropped head, ophthalmoplegia, tremor, involuntary movements, and cognitive impairments. The second patient showed a typical ALS phenotype and prominent adventitious movements. Genetic screening disclosed de novo p.P525L FUS mutation in the 2 patients by family cosegregation analysis. Muscle biopsy showed neurogenic patterns and numerous lipid droplets aggregating in the fibers.

Conclusion: Apart from the typical ALS phenotype, patients with p.P525L mutation in the FUS gene can present with great clinical heterogeneity including multiple movement disorders. Numerous lipid droplets in muscle fibers indicate that skeletal muscle is likely an important therapeutic target for ALS.
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http://dx.doi.org/10.1002/brb3.1625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303404PMC
June 2020