Two adjacent mutations on the dimer interface of SARS coronavirus 3C-like protease cause different conformational changes in crystal structure

AbstractThe 3C-like protease of SARS coronavirus (SARS-CoV 3CLpro) is vital for SARS-CoV replication and is a promising drug target. It has been extensively proved that only the dimeric enzyme is active. Here we discovered that two adjacent mutations (Ser139_Ala and Phe140_Ala) on the dimer interface resulted in completely different crystal structures of the enzyme, demonstrating the distinct roles of these two residues in maintaining the active conformation of SARS-CoV 3CLpro. S139A is a monomer that is structurally similar to the two reported monomers G11A and R298A. However, this mutant still retains a small fraction of dimer in solution, which might account for its remaining activity. F140A is a dimer with the most collapsed active pocket discovered so far, well-reflecting the stabilizing role of this residue. Moreover, a plausible dimerization mechanism was also deduced from structural analysis. Our work is expected to provide insight on the dimerization–function relationship of SARS-CoV 3CLpro

The clinical value of progestin-primed ovarian stimulation protocol for women with diminished ovarian reserve undergoing IVF/ICSI: a systematic review and meta-analysis

BackgroundTo determine whether progestin-primed ovarian stimulation (PPOS) is more effective for women with diminished ovarian reserve (DOR) than clomiphene citrate (CC)/letrozole (LE) plus gonadotropin in IVF or ICSI treatment.MethodsNine databases were searched until May 24, 2023, to identify relevant studies. Forest plots were used to present the results of this meta-analysis. Begg’s and Egger’s tests were applied to estimate publication bias. Subgroup and sensitivity analysis were performed to check the potential sources of heterogeneity and verify the robustness of the pooled results, respectively.ResultsA total of 14 studies with 4182 participants were included for meta-analysis. There was evidence of a statistically notable increase in clinical pregnancy rate (OR = 1.39, 95%CI [1.01, 1.91], p = 0.05), optimal embryos rate (OR = 1.50, 95%CI [1.20, 1.88], p = 0.0004), and cumulative pregnancy rate (OR = 1.73, 95%CI [1.14, 2.60], p = 0.009), the duration and the amount of gonadotropin required (MD = 1.56, 95%CI [0.47, 2.66], p = 0.005; SMD = 1.51, 95%CI [0.90, 2.12], p < 0.00001), along with decrease cycle cancellation rate (OR = 0.78, 95%CI [0.64, 0.95], p = 0.02), luteinizing hormone (LH) level on the day of hCG (SMD = -0.81, 95%CI [-1.10, -0.53], p < 0.00001), and premature LH surge rate (OR = 0.10, 95%CI [0.07, 0.15], p < 0.00001) when PPOS was used. No evidence for publication bias within results was revealed.ConclusionsBased on evidence-based results, PPOS protocol seems to improve IVF/ICSI outcomes for women with DOR. More research with larger sample sizes and rigorous designs are required to further explore the value of PPOS among women diagnosed with DOR.Systematic review registrationwww.crd.york.ac.uk, identifier CRD42023430202

Improved spatiotemporal resolution of anti-scattering super-resolution label-free microscopy via synthetic wave 3D metalens imaging

Super-resolution (SR) microscopy has dramatically enhanced our understanding of biological processes. However, scattering media in thick specimens severely limits the spatial resolution, often rendering the images unclear or indistinguishable. Additionally, live-cell imaging faces challenges in achieving high temporal resolution for fast-moving subcellular structures. Here, we present the principles of a synthetic wave microscopy (SWM) to extract three-dimensional information from thick unlabeled specimens, where photobleaching and phototoxicity are avoided. SWM exploits multiple-wave interferometry to reveal the specimen’s phase information in the area of interest, which is not affected by the scattering media in the optical path. SWM achieves ~0.42 λ/NA resolution at an imaging speed of up to 106 pixels/s. SWM proves better temporal resolution and sensitivity than the most conventional microscopes currently available while maintaining exceptional SR and anti-scattering capabilities. Penetrating through the scattering media is challenging for conventional imaging techniques. Remarkably, SWM retains its efficacy even in conditions of low signal-to-noise ratios. It facilitates the visualization of dynamic subcellular structures in live cells, encompassing tubular endoplasmic reticulum (ER), lipid droplets, mitochondria, and lysosomes

Emissive Platinum(II) Cages with Reverse Fluorescence Resonance Energy Transfer for Multiple Sensing

It is quite challenging to realize fluorescence resonance energy transfer (FRET) between two chromophores with specific positions and directions. Herein, through the self-assembly of two carefully selected fluorescent ligands via metal-coordination interactions, we prepared two tetragonal prismatic platinum(II) cages with a reverse FRET process between their faces and pillars. Bearing different responses to external stimuli, these two emissive ligands are able to tune the FRET process, thus making the cages sensitive to solvents, pressure, and temperature. First, these cages could distinguish structurally similar alcohols such as n-butanol, t-butanol, and i-butanol. Furthermore, they showed decreased emission with bathochromic shifts under high pressure. Finally, they exhibited a remarkable ratiometric response to temperature over a wide range (223–353 K) with high sensitivity. For example, by plotting the ratio of the maximum emission (I600/I480) of metallacage 4b against the temperature, the slope reaches 0.072, which is among the highest values for ratiometric fluorescent thermometers reported so far. This work not only offers a strategy to manipulate the FRET efficiency in emissive supramolecular coordination complexes but also paves the way for the future design and preparation of smart emissive materials with external stimuli responsiveness

A Chaperonin Subunit with Unique Structures Is Essential for Folding of a Specific Substrate

Type I chaperonins are large, double-ring complexes present in bacteria (GroEL), mitochondria (Hsp60), and chloroplasts (Cpn60), which are involved in mediating the folding of newly synthesized, translocated, or stress-denatured proteins. In Escherichia coli, GroEL comprises 14 identical subunits and has been exquisitely optimized to fold its broad range of substrates. However, multiple Cpn60 subunits with different expression profiles have evolved in chloroplasts. Here, we show that, in Arabidopsis thaliana, the minor subunit Cpn60β4 forms a heterooligomeric Cpn60 complex with Cpn60α1 and Cpn60β1–β3 and is specifically required for the folding of NdhH, a subunit of the chloroplast NADH dehydrogenase-like complex (NDH). Other Cpn60β subunits cannot complement the function of Cpn60β4. Furthermore, the unique C-terminus of Cpn60β4 is required for the full activity of the unique Cpn60 complex containing Cpn60β4 for folding of NdhH. Our findings suggest that this unusual kind of subunit enables the Cpn60 complex to assist the folding of some particular substrates, whereas other dominant Cpn60 subunits maintain a housekeeping chaperonin function by facilitating the folding of other obligate substrates

Primary pleomorphic liposarcoma of fallopian tube with recurrence: a case report and review of the literature

Liposarcoma, which develops in adipose tissue, is one of the most common soft tissue sarcomas. It appears mostly in the lower limbs, particularly in the thigh and limb girdles, followed by the upper extremities, thoracoabdominal wall, and the internal trunk and retroperitoneum. Pleomorphic liposarcoma (PLS), a rare subtype of liposarcoma is considered a highgrade malignancy

A Network Pharmacology Approach to Estimate Potential Targets of the Active Ingredients of Epimedium for Alleviating Mild Cognitive Impairment and Treating Alzheimer’s Disease

Background. The present study made use of a network pharmacological approach to evaluate the mechanisms and potential targets of the active ingredients of Epimedium for alleviating mild cognitive impairment (MCI) and treating Alzheimer’s disease (AD). Methods. The active ingredients of Epimedium were acquired from the Traditional Chinese Medicine System Pharmacology database, and potential targets were predicted using the TCMSP target module, SwissTargetPrediction, and PharmMapper database. Target proteins correlating with MCI and AD were downloaded from the GeneCards, DisGeNet, and OMIM databases. The common targets of Epimedium, MCI, and AD were identified using the Jvenn online tool, and a protein-protein interaction (PPI) network was constructed using the String database and Cytoscape. Finally, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the common targets was performed using DAVID, and molecular docking between active ingredients and target genes was modeled using AutoDock Vina. Results. A total of 20 active ingredients were analyzed, and 337 compound-related targets were identified for Epimedium. Out of 236 proteins associated with MCI and AD, 54 overlapped with the targets of Epimedium. The top 30 interacting proteins in this set were ranked by topological analysis. GO and KEGG enrichment analysis suggested that the common targets participated in diverse biological processes and pathways, including cell proliferation and apoptosis, inflammatory response, signal transduction, and protein phosphorylation through cancer pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, sphingolipid signaling pathway, FoxO signaling pathway, and TNF signaling pathway. Molecular docking analysis suggested that the 20 active ingredients could bind to the top 5 protein targets. Conclusions. The present study provides theoretical evidence for in-depth analysis of the mechanisms and molecular targets by which Epimedium protects against MCI, AD, and other neurodegenerative diseases and lays the foundation for pragmatic clinical applications and potential new drug development

NdhV subunit regulates the activity of type-1 NAD(P)H dehydrogenase under high light conditions in cyanobacterium Synechocystis sp PCC 6803

The cyanobacterial NAD(P)H dehydrogenase (NDH-1) complexes play crucial roles in variety of bioenergetic reactions. However, the regulative mechanism of NDH-1 under stressed conditions is still unclear. In this study, we detected that the NDH-1 activity is partially impaired, but the accumulation of NDH-1 complexes was little affected in the NdhV deleted mutant (Delta ndhV) at low light in cyanobacterium Synechocystis sp. PCC 6803. Delta ndhV grew normally at low light but slowly at high light under inorganic carbon limitation conditions (low pH or low CO2), meanwhile the activity of CO2 uptake was evidently lowered than wild type even at pH 8.0. The accumulation of NdhV in thylakoids strictly relies on the presence of the hydrophilic subcomplex of NDH-1. Furthermore, NdhV was co-located with hydrophilic subunits of NDH-1 loosely associated with the NDH-1L, NDH-1MS' and NDH-1M complexes. The level of the NdhV was significantly increased at high light and deletion of NdhV suppressed the up-regulation of NDH-1 activity, causing the lowered the photosynthetic oxygen evolution at pH 6.5 and high light. These data indicate that NdhV is an intrinsic subunit of hydrophilic subcomplex of NDH-1, required for efficient operation of cyclic electron transport around photosystem I and CO2 uptake at high lights

A Process-Oriented Approach to Identify Evolutions of Sea Surface Temperature Anomalies with a Time-Series of a Raster Dataset

It is important to consider where, when, and how the evolution of sea surface temperature anomalies (SSTA) plays significant roles in regional or global climate changes. In the comparison of where and when, there is a great challenge in clearly describing how SSTA evolves in space and time. In light of the evolution from generation, through development, and to the dissipation of SSTA, this paper proposes a novel approach to identifying an evolution of SSTA in space and time from a time-series of a raster dataset. This method, called PoAIES, includes three key steps. Firstly, a cluster-based method is enhanced to explore spatiotemporal clusters of SSTA, and each cluster of SSTA at a time snapshot is taken as a snapshot object of SSTA. Secondly, the spatiotemporal topologies of snapshot objects of SSTA at successive time snapshots are used to link snapshot objects of SSTA into an evolution object of SSTA, which is called a process object. Here, a linking threshold is automatically determined according to the overlapped areas of the snapshot objects, and only those snapshot objects that meet the specified linking threshold are linked together into a process object. Thirdly, we use a graph-based model to represent a process object of SSTA. A node represents a snapshot object of SSTA, and an edge represents an evolution between two snapshot objects. Using a number of child nodes from an edge’s parent node and a number of parent nodes from the edge’s child node, a type of edge (an evolution relationship) is identified, which shows its development, splitting, merging, or splitting/merging. Finally, an experiment on a simulated dataset is used to demonstrate the effectiveness and the advantages of PoAIES, and a real dataset of satellite-SSTA is used to verify the rationality of PoAIES with the help of ENSO’s relevant knowledge, which may provide new references for global change research

Analysis of the Choice of Operation Mode and Prognosis Factors of Patients with Tumors of the Lung Metastasis

Background and objective Concept of treatment for pulmonary metastatic tumor has been changed. The aim of this study is to analysis of the choice of operation mode and prognosis factors of patients with tumors of the lung metastasis. Methods The clinical data of 57 patients with pulmonary metastases who underwent operations from January 2006 to December 2009 were retrospectively analyzed. Difference of conventional open thoracic surgery and thoracoscope surgery was compared. The relationship between gender, age, type of surgery, disease-free interval (DFI), the number of metastatic tumor, the size of tumor, chemotherapy and prognosis was explored. Results Among the patients, there was no perioperative mortality. Postoperative 1-, 3-, 5-year survival rates were 81.3%, 46.5% and 29.2%, the median survival time was 33.8 months. Multivariate analysis showed that DFI, the number and diameter of metastasis tumor were independent prognostic factors. Conclusions Reasonable choice of surgical treatment can improve the survival of pulmonary metastatic tumor patient. Thoracoscopic surgery method is preferred. Operation effect of patients with tumor diameter less than 4 cm in solitary pulmonary metastasis has better effect