Many SARS-CoV-2 variants with naturally acquired mutations have emerged. These mutations can affect viral properties such as infectivity and immune resistance. Although the sensitivity of naturally occurring SARS-CoV-2 variants to humoral immunity has been investigated, sensitivity to human leukocyte antigen (HLA)-restricted cellular immunity remains largely unexplored. Here, we demonstrate that two recently emerging mutations in the receptor-binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429 and B.1.617) and Y453F (in B.1.1.298), confer escape from HLA-A24-restricted cellular immunity. These mutations reinforce affinity toward the host entry receptor ACE2. Notably, the L452R mutation increases spike stability, viral infectivity, viral fusogenicity, and thereby promotes viral replication. These data suggest that HLA-restricted cellular immunity potentially affects the evolution of viral phenotypes and that a further threat of the SARS-CoV-2 pandemic is escape from cellular immunity.

Key Points FMT was safely performed in SCT patients, with 3 complete responses and 1 partial response. Temporal microbiota dynamics seem linked to gut condition and effector regulatory T cells also increased during response to FMT.

The complete Freund's adjuvant (CFA)-induced arthritic rat model has extensively served as a laboratory model in the study of arthritic pain. However, the time courses of allodynia and hyperalgesia and the efficacies of different analgesics have not fully been analyzed in this model. Mechanical allodynia, thermal and joint hyperalgesia, and other disease development parameters (body weight, mobility, paw volume, and joint stiffness) were measured on postinoculation days (PIDs) 0 to 28 in rats. Acute analgesic efficacies of drugs were evaluated on PID 9 when degrees of allodynia, hyperalgesia, and joint stiffness in the ipsilateral paw reached almost the maximum, although those in the contralateral paw changed only slightly. In the ipsilateral paw, thermal hyperalgesia reached the maximum on PID 1, whereas mechanical allodynia and joint hyperalgesia progressively developed during the first 7 or 8 days, being tuned in to arthritis development. In the contralateral paw, thermal hyperalgesia never occurred, whereas mechanical allodynia and joint hyperalgesia developed after PID 11. Morphine and tramadol had full efficacies for all the pain parameters tested at sedation-inducing doses. Indomethacin and diclofenac significantly but partially improved thermal and joint hyperalgesia. Amitriptyline significantly reduced thermal and joint hyperalgesia only at sedation-inducing dose. Acetaminophen, carbamazepine, and gabapentin had, at the most, very small efficacies. In conclusion, the present study provided integrated information about the time course of pain and other disease development parameters in the CFA-induced arthritic rats, and clarified acute efficacies of different categories of analgesics for the allodynia and hyperalgesia.The complete Freund's adjuvant (CFA)-induced arthritic rat model has extensively served as a laboratory model in the study of arthritic pain. Mechanical allodynia, thermal hyperalgesia and pain on joint movement (joint hyperalgesia), which are prominent features in arthritic pain, have proved to be present in it (Tatsuo et al., 1994;Jasmin et al., 1998;Bertorelli et al., 1999). The time courses of their progression after the CFA inoculation, however, have not been fully analyzed. The first aim in the present study, therefore, was to provide integrated information about the time courses of pain (mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia) and other disease development (body weight, mobility, paw volume, and joint stiffness) parameters after the CFA inoculation into the single hind paw in rats. Surprisingly, there are no studies that have fully evaluated the analgesic efficacies of different categories of analgesics on mechanical allodynia, thermal hyperalgesia, and joint hyperalgesia in the CFA-induced arthritic rat model. The second aim in the present study, therefore, was to investigate this issue. Antipyretics (e.g., acetaminophen) and nonsteroidal anti-inflammatory drugs (e.g., indomethacin and diclofenac) are the first line drugs in the treatment of arth...

We cloned a cDNA for the rat Ic-opioid receptor from a rat thalamus cDNA library. The deduced amino actd sequence consists of 380 restdues with features shared by members of the G protein-coupled receptor family. The specific bmding of [3H]bremazocine to the membrane of COS-7 cells transfected with the cDNA was displaced by x-specific opioid ligands. but not by p-and S-specific Iigands. Xenopus oocytes injected with the m vitro transcribed mRNA responded to opioid hgands with the same subtype spectficity. Northern blot analysis demonstrated that Kc-optoid receptor mRNA is expressed in a regionally specific manner in rat brain.