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The COVID-19 pandemic has highlighted the need for new antiviral targets, as many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a highly promising antiviral target, as it plays a direct role in priming the spike protein before viral entry occurs. Further, unlike other targets such as ACE2, TMPRSS2 has no known biological role. Here we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we demonstrate that serine protease inhibitors camostat, nafamostat, and gabexate inhibit through a covalent mechanism. We further identify new non-covalent compounds as TMPRSS2 protease inhibitors, demonstrating the utility of a combined virtual and experimental screening campaign in rapid drug discovery efforts.
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Objective To investigate non-invasive and safe methods for positioning and assessing the functional areas of epilepsy patients secondary to cerebral hemisphere atrophy to reduce postoperative dysfunction.Methods Eight epilepsy patients with cerebral hemisphere atrophy,admitted to our hospital from March 2006 to April 2009,were chosen in our study; magnetoencephalography (MEG) and magnetic resonance diffusion tensor imaging (DTI) were combined to locate the functional areas and assess the functional compensation of these patients.Different surgical methods were adopted according to different results of the patients.All patients were followed up for 12-46 months,averaged 21.6 months.Results MEG could clearly position the cortical sensory,motor,language and visual functional areas of 5 patients,and the other 3 could only be conformed functional areas without clear boundary resulting from their bad cooperation.DTI successfully showed the shape of functional area cortical fibers,which helped the surgery in deciding the extent of resection.Modified hemispherectomy was performed in two patients,multi-lobe resection in five,and temporal lobe resection and hemisphere incision in one; muscles in the contralateral limb of surgery appeared short-term myodynamia weakness and recovery was achieved after rehabilitation exercise.No epileptic seizure was noted in all the patients,enjoying Engle Ⅰ grading.Conclusion Combination of MEG and DTI is a safe,noninvasive method for locating functional areas,could provide security protection for surgical treatment of patients with epilepsy secondary to cerebral hemisphere atrophy.
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<p><b>OBJECTIVE</b>To localize the language cortex associated with Chinese word processing by magnetic source imaging (MSI).</p><p><b>METHODS</b>Eight right-handed and one left-handed healthy native Chinese subjects were examined by magnetoencephalography (MEG) and a 1.5T magnetic resonance imaging (MRI) unit. All subjects were given pure tone stimuli 50 times, 150 pairs of Chinese words (meaning related or unrelated) auditory stimuli, and pure tone stimuli subsequently 50 times. Evoked response fields time locked to the pure tone and Chinese words were recorded using a whole-head neuromagnetometer in real-time. The acquired data were averaged by the acquisition computer according to the response to the pure tone, related pairs of words and unrelated pairs of words. The data obtained by MEG were superimposed on MRI, using a GE Signa 1.5T system.</p><p><b>RESULTS</b>MEG, showed there were two obviously higher magnetic waves named M50 and M100, which were localized in the bilateral transverse temporal gyri in all subjects. The responses to the pairs of Chinese words (meaning related or unrelated) were similar in the same hemisphere of the same subjects. There was a higher peak during 300 - 600 ms in the right hemisphere of one left handed subject, but no peak in the left hemisphere, indicating that the language dominant hemisphere was localized in the right hemisphere. Superimposing the MEG data on MRI, the language area was localized in the Wernicke's areas. A 300 - 600 ms response peak was obsarved in each hemisphere (the amplitude of the 300 - 600 ms response peak in each hemisphere was almost the same) in two right-handed subjects, showing that the language area was localized in the 2 hemispheres in the two subjects. There was one peak in each hemisphere (300 - 600 ms response) in 6 subjects, but the amplitude of the wave in the left hemisphere in the 6 subjects was much higher than that in the right hemisphere. By choosing randomly from the later component (300 - 600 ms response) several time points and superimposing them on MRI, all time points were localized in the posterior part of the superior temporal gyri, which is the Wernicke's areas.</p><p><b>CONCLUSIONS</b>Comparing with the later component of the bilateral hemispheres, the wave amplitude in the language dominant hemisphere was much higher than that in the non-language dominant hemisphere. The language areas could be identified by judging whether meanings of pairs of Chinese words were related or not.</p>
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Adolescent , Adult , Female , Humans , Male , Cerebral Cortex , Language , Magnetic Resonance Imaging , MagnetoencephalographyABSTRACT
0.05). Conclusions The primary auditory cortex could be precisely localized by MSI.
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Objective To evaluate the epileptic focus localization value of MSI in patients with refractory epilepsy and encephalomalacia. Method MSI examination was proceeded in 11 patients with refractory epilepsy and encephalomalacia. Five of them were treated with gamma-knife; the others were treated with surgery. Results In the five patients treated with gamma-knife, the result was satisfied in 3 patients, one patient improved significantly, the other one useless. The distance between the encephalomalacia and the epileptic focus was 4cm in one patient; one patient′s encephalomalacia was located in right frontal-parietal lobe but the epileptic focus mainly located in right temporal lobe, only a little located around the encephalomalacia. Overall agreement among VEEG,ECoG and MEG (presence of concordant spikes with the same localization shown by three techniques) was obtained in three patients, the areas localized by ECoG were larger than VEEG and MSI in two patients. The localization was different in VEEG, MSI and ECoG in one patient, then he was given a resection of bilateral occipital epileptic focus. The results of patients treated with surgery were satisfied. Conclusion The MSI localization of epileptic focus in patients with refractory epilepsy and encephalomalacia is precise, and it can direct the advanced clinical treatment.