Guided by the theory of turbid pathogen disturbing clarity， this paper holds that the pathogenesis of otolith disorders involves the failure of clear yang to ascend and the internal generation of phlegm-turbidity as the initiating factors. The clinical manifestations are characterized by the intermingling of phlegm and fluid， as well as the disturbance between turbid and clear substances， while the root lies in spleen-kidney deficiency and depletion of primordial qi. Treatment strategies are formulated according to the different stages of the disease： in the acute phase， therapy focuses on warming and resolving phlegm-fluid retention， using a modified combination of Linggui Zhugan Decoction （苓桂术甘汤） and Zexie Decoction （泽泻汤）； in the residual phase， the approach shifts to tonifying qi and uplifting clear yang， with a modified combination of Shengxian Decoction （升陷汤） and Shengmai Power （生脉散）； in the consolidation phase， therapy aims to tonify the kidney and replenish essence， employing a modified version of Qiju Dihuang Pill （杞菊地黄丸）.

Objective:To explore the short-term outcomes of 3D-printing stand-alone artificial vertebral body(AVB)in the surgical procedure of anterior cervical corpectomy and fusion(ACCF).Methods:Following the proposal of IDEAL(idea,development,exploration,assessment,and long-term follow-up)framework,we designed and conducted this single-armed,retrospective cohort study.The patients with cervical spondylotic myelopathy were recruited,and these patients exclusively received the surgical procedure of single-level ACCF in our single center.After the process of corpectomy,the size was tailored using different trials and the most suitable stand-alone AVB was then implanted.This AVB was manufactured by the fashion of 3D-printing.Two pairs of screws were inserted in an inclined way into the adjacent vertebral bodies,to stabilize the AVB.The participants were regularly followed-up after the operation.Their clinical data were thoroughly reviewed.We assessed the neurological status according to Japanese Orthopedic Association(JOA)scale.We determined the fusion based on imaging examination six months after the operation.The recorded clinical data were analyzed using specific software and they presented in suitable styles.Paired t test was employed in comparison analysis.Results:In total,there were eleven patients being recruited eventually.The patients were all followed up over six months after the operation.The mean age of the cohort was(57.2±10.2)years.The mean operation time was(76.1±23.1)min and the median bleeding volume was 150(100,200)mL.The postoperative course was uneventful for all the cases.Dysphagia,emergent hematoma,and deterioration of neurological func-tion did not occur.Mean JOA scores were 13.2±2.2 before the operation and 16.3±0.8 at the final follow-up,which were significantly different(P＜0.001).The mean recovery rate of neurological func-tion was 85.9％.By comparing the imaging examinations postoperatively and six months after the opera-tion,we found that the average subsidence length was(1.2±1.1)mm,and that there was only one ca-ses(9.1％)of the severe subsidence(＞3 mm).We observed significant improvement of cervical lor-dosis after the operation(P=0.013).All the cases obtained solid fusion.Conclusion:3D-printing stand-alone AVB presented favorable short-term outcome in one-level ACCF in this study.The fusion rate of this zero-profile prosthesis was satisfactory and the complication rate was relatively low.

The adenosine 5'-triphosphate (ATP)-binding cassette (ABC) transporter, IrtAB, plays a vital role in the replication and viability of Mycobacterium tuberculosis (Mtb), where its function is to import iron-loaded siderophores. Unusually, it adopts the canonical type IV exporter fold. Herein, we report the structure of unliganded Mtb IrtAB and its structure in complex with ATP, ADP, or ATP analogue (AMP-PNP) at resolutions ranging from 2.8 to 3.5 Å. The structure of IrtAB bound ATP-Mg2+ shows a "head-to-tail" dimer of nucleotide-binding domains (NBDs), a closed amphipathic cavity within the transmembrane domains (TMDs), and a metal ion liganded to three histidine residues of IrtA in the cavity. Cryo-electron microscopy (Cryo-EM) structures and ATP hydrolysis assays show that the NBD of IrtA has a higher affinity for nucleotides and increased ATPase activity compared with IrtB. Moreover, the metal ion located in the TM region of IrtA is critical for the stabilization of the conformation of IrtAB during the transport cycle. This study provides a structural basis to explain the ATP-driven conformational changes that occur in IrtAB.
Siderophores/metabolism* ; Iron/metabolism* ; Mycobacterium tuberculosis/metabolism* ; Cryoelectron Microscopy ; Adenosine Triphosphate/metabolism* ; ATP-Binding Cassette Transporters

Lymphocytic choriomeningitis virus/physiology* ; Allosteric Regulation ; Nucleotidyltransferases

Heme/metabolism* ; Cryoelectron Microscopy ; Membrane Transport Proteins ; Escherichia coli Proteins/metabolism*

Antiviral Agents/pharmacology* ; COVID-19 ; Coronavirus 3C Proteases ; Humans ; Lactams ; Leucine ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Nitriles ; Proline ; Protease Inhibitors/pharmacology* ; SARS-CoV-2

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use* ; Binding Sites ; COVID-19/virology* ; Coronavirus Papain-Like Proteases/metabolism* ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Drug Repositioning ; High-Throughput Screening Assays/methods* ; Humans ; Imidazoles/therapeutic use* ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Naphthoquinones/therapeutic use* ; Protease Inhibitors/therapeutic use* ; Protein Structure, Tertiary ; Recombinant Proteins/isolation & purification* ; SARS-CoV-2/isolation & purification*

Inhibition of Mycobacterium tuberculosis (Mtb) cell wall assembly is an established strategy for anti-TB chemotherapy. Arabinosyltransferase EmbB, which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis. Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug, ethambutol. Herein, we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its "resting state" and DPA-bound "active state". EmbB is a fifteen-transmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrier-protein (AcpM) on their cytoplasmic surface. Conformational changes upon DPA binding indicate an asymmetric movement within the EmbB dimer during catalysis. Functional studies have identified critical residues in substrate recognition and catalysis, and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA. The structures represent the first step directed towards a rational approach for anti-TB drug discovery.

Objective To evaluate the diagnostic performance of plasma miR-499 in acute myocardial infarction (AMI) diagnosis.Methods Diagnostic accuracy test.The suspected AMI patients,who with chest pain for more than half an hour and been admitted in the Second People's Hospital of Wuxi and First People's Hospital of chuzhou during October 2010 and July 2011,were consecutively and prospectively enrolled in the present study.Sixty apparently healthy individuals were designed as healthy control.The plasma samples of the suspected AMI patients were collected within two hours after admission.The plasma miR-499 was determined by real time polymerase chain reaction (RT-PCR).The diagnostic performance of plasma miR-499 for AMI was estimated by receiver operating characteristic (ROC) curve analysis.The association between plasma miR-499 and AMI was analyzed by multivariable logistic model.The plasma miR-499 was determined and explained in blind fashion.Results Two hundred and nine suspected AMI patients,including 131 confirmed AMI patients (46 STEMI and 85 NSTEMI) and 78 AMI free patients were enrolled in the present study.The delta cycle threshold (ΔCT) was 1.01 ± 3.34 for AMI patients,-2.76 ± 2.90 for non-AMI patients and-3.79 ± 2.21 for healthy controls.The differences had statistical significance (x2 =96.77,P ＜ 0.01).The area under curve (AUC) of plasma miR-499 was 0.80 (95％ C I:0.74-0.86),lower than that of cardiac troponin Ⅰ (AUC =0.90,95％ CI:0.86-0.94) on admission (P ＜0.01).At the optimal cut-off of 0.18,the diagnostic sensitivity and specificity were 0.69 (95％ CI:0.61-0.77) and 0.77 (95％ CI:0.66-0.86),respectively.The coefficient of correlation between plasma miR-499 and cTnI was 0.72 (P ＜0.01).The odds ratio (OR) of plasma miR-499 ＞0.18 for AMI was 2.59 (95％ CI:1.10-6.07),after adjusted cTnI.Conclusions Plasma miR-499 is a useful biomarker for AMI diagnosis.It can provide additional diagnostic information beyond cTnI.Combination utility of plasma miR-499 and cTnI may improve the diagnostic accuracy for AMI.