Performance and Analysis of the Alchemical Transfer Method for Binding Free Energy Predictions of Diverse Ligands

The Alchemical Transfer Method (ATM) is herein validated against the relative binding free energies of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and the AToM-OpenMM software to compute the relative binding free energies (RBFE) of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical relative binding free energy methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and post-corrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 relative binding free energy calculations for eight protein targets and found that ATM achieves accuracy comparable to existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM is applicable as a production tool for relative binding free energy (RBFE) predictions across a wide range of perturbation types within a unified, open-source framework

Antifouling Double-Skinned Forward Osmosis Membranes by Constructing Zwitterionic Brush-Decorated MWCNT Ultrathin Films

Pressure retarded osmosis (PRO) process is hindered by severe fouling occurring within the porous support of the forward osmosis (FO) membranes. We designed a novel double-skinned FO membrane containing a polyamide salt-rejecting layer and a zwitterionic brush-decorated, multiwalled carbon nanotube (MWCNT/PSBMA) foulant-resisting layer on the back side. Our results demonstrated that the coating of the MWCNT/PSBMA layer on the porous polyketone (PK) support imparted enhanced hydrophilicity and smaller membrane pore size, thereby providing excellent resistance toward both protein adhesion and bacterial adsorption. We also further evaluated this resultant double-skinned membrane (i.e., TFC-MWCNT/PSBMA) in dynamic PRO fouling experiments using protein and alginate as model organic foulants. Compared to the pristine TFC-PK and hydrophobic TFC-MWCNT membranes, the TFC-MWCNT/PSBMA membrane exhibited not only the lowest water flux decline but also the highest water flux recovery after simple physical flushing. These results shed light on fabrication of antifouling PRO membranes for water purification purposes

Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with outcomes in stroke patients achieving successful recanalization by endovascular thrombectomy

ObjectiveSerum inflammatory biomarkers play crucial roles in the development of acute ischemic stroke (AIS). In this study, we explored the association between inflammatory biomarkers including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), and clinical outcomes in AIS patients who achieved successful recanalization.MethodsPatients with AIS who underwent endovascular thrombectomy (EVT) and achieved a modified thrombolysis in the cerebral infarction scale of 2b or 3 were screened from a prospective cohort at our institution between January 2013 and June 2021. Data on blood parameters and other baseline characteristics were collected. The functional outcome was an unfavorable outcome defined by a modified Rankin Scale of 3–6 at the 3-month follow up. Other clinical outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality. Multivariable logistic regression analysis was performed to evaluate the effects of PLR, NLR, and MLR on clinical outcomes.ResultsA total of 796 patients were enrolled, of which 89 (11.2%) developed sICH, 465 (58.4%) had unfavorable outcomes at 3 months, and 168 (12.1%) died at the 3-month follow up. After adjusting for confounding variables, a higher NLR (OR, 1.076; 95% confidence interval [CI], 1.037–1.117; p < 0.001) and PLR (OR, 1.001; 95%CI, 1.000–1.003; p = 0.045) were significantly associated with unfavorable outcomes, the area under the receiver operating characteristic curve of NLR and PLR was 0.622 and 0.564, respectively. However, NLR, PLR, and MLR were not independently associated with sICH and 3-month mortality (all adjusted p > 0.05).ConclusionOverall, our results indicate that higher PLR and NLR were independently associated with unfavorable functional outcomes in AIS patients with successful recanalization after EVT; however, the underlying mechanisms are yet to be elucidated

Taguchi and ANOVA analysis for the optimization of the microencapsulation of a volatile phase change material

The microencapsulation of volatile phase change materials is an important and challenging area for low-temperature thermal energy storage. Our previous studies have effectively addressed the challenge of long-term volatile core retention and also indicated that the quality of the obtained poly(urea-formaldehyde) microcapsules is highly affected by various process parameters, including reaction temperature, initial pH, reaction time, and homogenization speed. In this paper, the Taguchi orthogonal array has been employed to optimise controllable process parameters to identify the most synergistic combination, in order to maximise the payload, yield, and encapsulation efficiency. The Taguchi signal-to-noise ratio results substantiated that the most efficient combination of parameters was 3 h reaction time, pH 3.5, 55 °C reaction temperature, and 1200 rpm homogenization speed. With this combination of parameters, microcapsules with superbly high payload of 95.2%, as well as a yield of 30.5% and encapsulation efficiency of 71.1% were amalgamated. In addition, Analysis of Variance (ANOVA) was also utilised to demonstrate the mean response magnitudes (% contribution) of each of the four controllable process parameters, in terms of contribution for the payload, yield, and encapsulation efficiency. Overall, it was indicated that the temperature is the most influential parameter at 83.1% contribution, followed by pH at 6.8%, reaction time at 5.2%, and homogenization speed at 4.9%. Such findings in this work postulate the fundamental insights into maximising the output of the formulation conditions, which in turn is aimed to minimise the time and cost of production of the microcapsules

MSPoisDM: A Novel Peptide Identification Algorithm Optimized for Tandem Mass Spectra

Tandem mass spectrometry (MS/MS) plays an extremely important role in proteomics research. Thousands of spectra can be generated in modern experiments, how to interpret the LC-MS/MS is a challenging problem in tandem mass spectra analysis. Our peptide identification algorithm, MSPoisDM, is integrated the intensity information which produced by target-decoy statistics, although intensity information often undervalued. Furthermore, in order to combine the intensity information for better, we propose a novel concept scoring model which based on Poisson distribution. Compared with commonly used commercial software Mascot and Sequest at 1% FDR, the results show MSPoisDM is robust and versatile for various datasets which obtained from different instruments. We expect our algorithm MSPoisDM will be broadly applied in the proteomics studies

Where are we heading in post-China angioplasty and stenting for symptomatic intracranial severe stenosis era?

Symptomatic intracranial atherosclerotic disease (ICAD) is a globally challengeable disease. In the past 20 years, people have made a huge effort to deal with the problem including using endovascular technology and aggressive medical therapy. However, the efficacy of these methods seemed to be limited. The recent China angioplasty and stenting for symptomatic intracranial severe stenosis (CASSISS) did not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe ICAD. So where are we heading in the post-CASSISS era

Enriched Environment Promotes Cognitive Function Recovery following Cerebral Ischemic Injury via Upregulating GABAergic and Glutamatergic Systems in the Contralateral Hippocampus

Poststroke cognitive impairment severely affects the long-term recovery of patients. However, it remains unknown whether an enriched environment can remodel contralateral hippocampal function and promote cognitive function recovery after cerebral ischemic injury. To further explore, 36 C57BL/6 mice that underwent permanent middle cerebral artery occlusion (pMCAO) were randomly assigned to three groups: enriched environment (EE), standard condition (SC), and sham surgery (Sham). After 21 days of intervention, the Morris water maze and step-through test was utilized for testing the cognitive function of the mice, cresyl violet staining for measuring the degree of atrophy in the hippocampal tissues, and western blotting for quantitating the expression levels of GA1B, GAD67, and NR2B, and immunohistochemistry for levels of NR2B in the CA1 region of the contralateral hippocampus. The results showed that cognitive function-related behavioral performance decreased in the SC group, and performance was better in the EE group than that in the SC group (p  0.05); levels of GA1B, GAD67, and NR2B in the contralateral hippocampus were significantly higher in the EE group than those in the SC group (p < 0.01); and the level of NR2B in the CA1 region of the contralateral hippocampus significantly increased in the EE group compared to the SC group (p < 0.01). We believe that contralateral hippocampal function is inhibited after cerebral ischemic injury, further affecting cognitive function. However, enriched environment can upregulate GABAergic and glutamatergic systems in the contralateral hippocampus to promote cognitive function recovery after cerebral ischemic injury

Mirror Image of Spontaneous Intracranial Hemorrhage

In this paper, we reported the first case of mirrored spontaneous intracranial hemorrhage with almost identical hematoma morphological characteristics. This patient’s first symptom was loss of consciousness, without any local neurological symptoms. This clinical presentation fits well with the atypical computed tomography (CT) image showing bilateral hematomas, and indicates that the distribution of hypertensive vascular damage may be symmetric and that the degree of the bilateral lesions may be similar