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In late 2023, several SARS-CoV-2 XBB descendants, notably EG.5.1, were predominant worldwide. However, a distinct SARS-CoV-2 lineage, the BA.2.86 variant, also emerged. BA.2.86 is phylogenetically distinct from other Omicron sublineages, accumulating over 30 amino acid mutations in its spike protein. Here, we examined the virological characteristics of the BA.2.86 variant. Our epidemic dynamics modeling suggested that the relative reproduction number of BA.2.86 is significantly higher than that of EG.5.1. Additionally, four clinically available antivirals were effective against BA.2.86. Although the fusogenicity of BA.2.86 spike is similar to that of the parental BA.2 spike, the intrinsic pathogenicity of BA.2.86 in hamsters was significantly lower than that of BA.2. Since the growth kinetics of BA.2.86 are significantly lower than those of BA.2 both in vitro and in vivo, the attenuated pathogenicity of BA.2.86 is likely due to its decreased replication capacity. These findings uncover the features of BA.2.86, providing insights for control and treatment., Competing Interests: Declaration of interests J.I. has consulting fees and honoraria for lectures from Takeda Pharmaceutical Co. Ltd. K. Sato has consulting fees from Moderna Japan Co., Ltd. and Takeda Pharmaceutical Co. Ltd. and honoraria for lectures from Gilead Sciences, Inc., Moderna Japan Co., Ltd., and Shionogi & Co., Ltd., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Most mammalian cells prevent viral infection and proliferation by expressing various restriction factors and sensors that activate the immune system. Several host restriction factors that inhibit human immunodeficiency virus type 1 (HIV-1) have been identified, but most of them are antagonized by viral proteins. Here, we describe CCHC-type zinc-finger-containing protein 3 (ZCCHC3) as a novel HIV-1 restriction factor that suppresses the production of HIV-1 and other retroviruses, but does not appear to be directly antagonized by viral proteins. It acts by binding to Gag nucleocapsid (GagNC) via zinc-finger motifs, which inhibits viral genome recruitment and results in genome-deficient virion production. ZCCHC3 also binds to the long terminal repeat on the viral genome via the middle-folded domain, sequestering the viral genome to P-bodies, which leads to decreased viral replication and production. This distinct, dual-acting antiviral mechanism makes upregulation of ZCCHC3 a novel potential therapeutic strategy., Competing Interests: J.F.H. has received research support, paid to Northwestern University, from Gilead Sciences and is a paid consultant for Merck., (© 2024 The Author(s).)

Pigs are important animals for meat production but can carry several zoonotic diseases, including the Japanese encephalitis virus, Nipah virus, and influenza viruses. Several Orthomyxoviridae and Coronavirinae respiratory viruses require cleavage of envelope proteins to acquire viral infectivity and consequently, need a host protease or the addition of exogenous trypsin for efficient propagation. Host TMPRSS2 is a key protease responsible for viral cleavage. Stable expression of human TMPRSS2 in African green monkey-derived Vero cells can enhance the porcine epidemic diarrhea virus. However, considering the narrow host tropism of viruses, a porcine cell line expressing pig TMPRSS2 could be optimal for replicating pig-derived viruses. Herein, we generated and evaluated a pig-derived PK-15 cell line stably expressing pig TMPRSS2. This cell line markedly (>1000-fold) and specifically enhanced the growth of influenza viruses. Furthermore, we demonstrated the usefulness of a PK-15 cell line lacking the Stat2 gene with a stable expression of pig TMPRSS2 for efficient virus isolation from clinical samples in the presence of type I interferons. Therefore, PK-15 cells expressing pig TMPRSS2 could be a valuable and promising tool for virus isolation, vaccine production, and virological studies of TMPRSS2-dependent viruses.

Recent studies have revealed the unique virological characteristics of Omicron, particularly those of its spike protein, such as less cleavage efficacy in cells, reduced ACE2 binding affinity, and poor fusogenicity. However, it remains unclear which mutation(s) determine these three virological characteristics of Omicron spike. Here, we show that these characteristics of the Omicron spike protein are determined by its receptor-binding domain. Of interest, molecular phylogenetic analysis revealed that acquisition of the spike S375F mutation was closely associated with the explosive spread of Omicron in the human population. We further elucidated that the F375 residue forms an interprotomer pi-pi interaction with the H505 residue of another protomer in the spike trimer, conferring the attenuated cleavage efficiency and fusogenicity of Omicron spike. Our data shed light on the evolutionary events underlying the emergence of Omicron at the molecular level., Competing Interests: The authors declare that no competing interests exist., (© 2022 The Authors.)

Human immunodeficiency virus type 1 (HIV-1)-based lentiviral vectors are indispensable tools for gene engineering in mammalian cells. Conversely, lentiviral vector transduction is severely inhibited in bovine cells. Previous studies demonstrated that this inhibition is caused by the anti-lentiviral host factor tripartite motif containing 5 (TRIM5), which targets incoming HIV-1 virions by interacting with the viral capsid. In this study, we investigated several methods for overcoming the limited applicability of lentiviral vectors in bovine cells. First, we demonstrated that the SPRY domain of bovine TRIM5 is the major determinant of anti-viral activity. Second, we found that mutations that allow the capsid to evade rhesus macaque TRIM5α minimally rescued HIV-1 infectivity in bovine-derived MDBK cells. Third, we found that cyclosporine A, which relieves the inhibition of HIV-1 infection in monkey cells, significantly rescued the impaired HIV-1 infectivity in MDBK cells. Lastly, we successfully generated a bovine cell line lacking intact TRIM5 using the CRISPR/Cas9 technique. This TRIM5 knockout cell line displayed significantly higher susceptibility to an HIV-1-based lentiviral vector. In conclusion, our findings provide a promising gene engineering strategy for bovine cells, thereby contributing to innovations in agriculture and improvements in animal health., (© 2022. The Author(s).)

With the current worldwide pandemic of COVID-19, there is an urgent need to develop effective treatment and prevention methods against SARS-CoV-2 infection. We have previously reported that the proanthocyanidin (PAC) fraction in blueberry (BB) leaves has strong antiviral activity against hepatitis C virus (HCV) and human T-lymphocytic leukemia virus type 1 (HTLV-1). In this study, we used Kunisato 35 Gou (K35) derived from the rabbit eye blueberry (Vaccinium virgatum Aiton), which has a high PAC content in the leaves and stems. The mean of polymerization (mDP) of PAC in K35 was the highest of 7.88 in Fraction 8 (Fr8) from the stems and 12.28 of Fraction 7 (Fr7) in the leaves. The composition of BB-PAC in K35 is that most are B-type bonds with a small number of A-type bonds and cinchonain I as extension units. A strong antiviral effect was observed in Fr7, with a high polymerized PAC content in both the leaves and stems. Furthermore, when we examined the difference in the action of BB-PAC before and after SARS-CoV-2 infection, we found a stronger inhibitory effect in the pre-infection period. Moreover, BB-PAC Fr7 inhibited the activity of angiotensin II converting enzyme (ACE2), although no effect was observed in a neutralization test of pseudotyped SARS-CoV-2. The viral chymotrypsin-like cysteine protease (3CLpro) of SARS-CoV-2 was also inhibited by BB-PAC Fr7 in leaves and stems. These results indicate that BB-PAC has at least two different inhibitory effects, and that it is effective in suppressing SARS-CoV-2 infection regardless of the time of infection., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Soon after the emergence and global spread of the SARS-CoV-2 Omicron lineage BA.1, another Omicron lineage, BA.2, began outcompeting BA.1. The results of statistical analysis showed that the effective reproduction number of BA.2 is 1.4-fold higher than that of BA.1. Neutralization experiments revealed that immunity induced by COVID vaccines widely administered to human populations is not effective against BA.2, similar to BA.1, and that the antigenicity of BA.2 is notably different from that of BA.1. Cell culture experiments showed that the BA.2 spike confers higher replication efficacy in human nasal epithelial cells and is more efficient in mediating syncytia formation than the BA.1 spike. Furthermore, infection experiments using hamsters indicated that the BA.2 spike-bearing virus is more pathogenic than the BA.1 spike-bearing virus. Altogether, the results of our multiscale investigations suggest that the risk of BA.2 to global health is potentially higher than that of BA.1., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

During the current coronavirus disease 2019 (COVID-19) pandemic, a variety of mutations have accumulated in the viral genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, at the time of writing, four variants of concern are considered to be potentially hazardous to human society 1 . The recently emerged B.1.617.2/Delta variant of concern is closely associated with the COVID-19 surge that occurred in India in the spring of 2021 (ref. 2 ). However, the virological properties of B.1.617.2/Delta remain unclear. Here we show that the B.1.617.2/Delta variant is highly fusogenic and notably more pathogenic than prototypic SARS-CoV-2 in infected hamsters. The P681R mutation in the spike protein, which is highly conserved in this lineage, facilitates cleavage of the spike protein and enhances viral fusogenicity. Moreover, we demonstrate that the P681R-bearing virus exhibits higher pathogenicity compared with its parental virus. Our data suggest that the P681R mutation is a hallmark of the virological phenotype of the B.1.617.2/Delta variant and is associated with enhanced pathogenicity., (© 2021. The Author(s).)

SARS-CoV-2 Lambda, a variant of interest, has spread in some South American countries; however, its virological features and evolutionary traits remain unclear. In this study, we use pseudoviruses and reveal that the spike protein of the Lambda variant is more infectious than that of other variants due to the T76I and L452Q mutations. The RSYLTPGD246-253N mutation, a unique 7-amino acid deletion in the N-terminal domain of the Lambda spike protein, is responsible for evasion from neutralizing antibodies and further augments antibody-mediated enhancement of infection. Although this mutation generates a nascent N-linked glycosylation site, the additional N-linked glycan is dispensable for the virological property conferred by this mutation. Since the Lambda variant has dominantly spread according to the increasing frequency of the isolates harboring the RSYLTPGD246-253N mutation, our data suggest that the RSYLTPGD246-253N mutation is closely associated with the substantial spread of the Lambda variant in South America., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Excessive pressure and shear stress while walking cause a risk of callus formation, which eventually causes foot ulcers in patients with diabetes mellitus. Callus under the second metatarsal head (MTH) has been associated with increased shear stress/pressure ratios (SPR). Callus under the fifth MTH has been associated with increased peak shear stress (PSS). The purpose of this study is to examine whether the effect of the suitable size and width of shoes prevents diabetic foot ulcers under the second and fifth MTH. We measured the pressure and shear stress by testing three kinds of sizes and two types of width of shoes. Significant difference was not observed in the SPR under the second MTH among different sizes of shoes. However, the pressure and shear stress were significantly lower when putting on shoes of fit size compared with larger sizes. The PSS under the fifth MTH was significantly smaller when putting on shoes of fit width compared with those of narrow width. Wearing shoes of fit size and width has the potential to prevent callus formation by reducing the pressure and shear stress constituting SPR under the second MTH and PSS under the fifth MTH.

Background: Nursing care performed during sleep, including nurse-assisted patient turning, is one of the factors that deteriorates sleep quality but is necessary for pressure ulcer prevention. Thus, it is important to determine when nurseassisted patient turning has the least impact on sleep quality., Aim: The aim of this study was to clarify the impact of nurseassisted patient turning at different sleep stages and to determine the optimal timing of this aspect during sleep., Methods: The experiment, which consisted of healthy men in their 20s and 30s, was performed over four successive nights per subject. The first night was dedicated to environment adaptation, and the 2nd to the 4th nights were randomly assigned for shallow sleep intervention, deep sleep intervention, and non-intervention. On the intervention day, nurse-assisted patient turning was conducted twice. Overnight sleep conditions were measured by polysomnography (PSG). The PSG waveform transmitted to a tablet was analyzed in real time to determine the stage of sleep. The patient was turned when he entered the planned stage of sleep., Results: The study analyzed fourteen (14) subjects. Shallow sleep time, deep sleep time, and sleep resumption time after nurse-assisted patient turning were compared among the three groups of non-intervention day, shallow sleep intervention day and deep sleep intervention day. There was no significant difference in the shallow and deep sleep time among the three groups. However, sleep resumption time after nurse-assisted patient turning was significantly shorter on the deep sleep intervention day than on the shallow sleep intervention day (p = textbf 0.033)., Conclusions: This study has novelty in examining the impact of nurse-assisted patient turning performed at different sleep stages on subsequent sleep using objective indicators. The study suggested that a deep sleep state is the optimal timing of nurseassisted patient turning due to the short time to sleep resumption.

Introduction: Callus is one of the main causes of diabetic foot ulcers. Therefore, preventing callus formation is very important. In a previous study, it was clarified that callus formation under the first metatarsal head (MTH) is associated with high shear stress time integral/pressure time integral (SPR-i). another study, it was clarified that rocker sole shoes are effective in reducing peak pressure under the first MTH. Therefore, we hypothesized that rocker sole shoes reduce SPR-i under the first MTH. This study aimed to clarify the effect of rocker sole shoes for external forces and leg motions in comparison with that of the normal sole shoes., Methods: In-shoe external forces and leg motions were measured during walking wearing the normal sole shoes or the rocker sole shoes in healthy participants. As the external forces, the peak plantar pressure (PP), pressure time integral (PI), peak shear stress (PSS), and shear stress integral (SSI) of each gait cycle were calculated. Additionally, shear stress-pressure ratios (SPR) were calculated by dividing shear stress by pressure; concretely, peak values (SPR-p) and time integral values (SPR-i). As the leg motion, hip and knee joint motions were analyzed for the axis of flexion- extension. Three axes of ankle joint motion (inversion-eversion, plantar flexion-dorsiflexion, and adduction-abduction) were analyzed., Results and Discussion: Six participants attended, and twelve feet were analyzed. When wearing the rocker sole shoes, the SPR-i under the first MTH was significantly smaller than when wearing the normal sole shoes. The SPR-i higher than 0.60 is associated with callus formation under the first MTH. In three of five feet with callus, SPR-i exceeded 0.60 in the normal sole shoes. The SPR-i of all three feet became smaller than 0.60 when wearing the rocker sole shoes. Although the knee (flexion-extension) and ankle (plantar flexion-dorsiflexion) joint motion became smaller when wearing the rocker sole shoes, there was no significant difference in walking speed. It is considered that propulsion was maintained by the push-off support provided by rocker sole shoes., Conclusion: It was suggested that rocker sole shoes are effective preventing callus formation under the first MTH.

This study aimed to examine the extent to which a familiar voice influences brain activity. Participants were nine healthy female volunteers aged 21-34 years old (with a mean age of 25.78 ± 4.04 years). Brain activity was recorded during periods of silence, familiar and unfamiliar voices. Electroencephalographic data were collected and analyzed using a frequency rate set at 5 min. To account for emotional influences imbedded into the contents of the voice stimuli, both the voice of a familiar family member and the voice of a stranger were used to record a well-known Japanese fairy tale, 'Momotaro'. Results revealed that listening to familiar voices increased the rate of the β band (13-30 Hz) in all four brain areas (F3, F4, C3 and C4). In particular, increased activity was observed at F4 and C4. Findings revealed that in study, participants' familiar voices activated cerebral functioning more than unfamiliar voices., (© 2012 Blackwell Publishing Asia Pty Ltd.)

Artificial sources of illumination can be easily used, regardless of the time and place, to improve visibility at night and in dark places. Illuminance and color temperature are particularly important factors since they are known to elicit physiological effects. However, the relationship between changes in illuminance and somatosensory function has not been sufficiently clarified. Thus, the purpose of this study was to construct a laboratorial model to examine the effects of lowering or raising illuminance on somatosensory function. Three illuminance levels (200 lx, 50 lx, and 0 lx), which were changed using all combinations, and an artificial sensory stimulus maintained at a constant intensity were presented to the subjects of this study. Objective sensory function in response to the sensory stimulus was investigated by somatosensory evoked potential (SEP), and subjective sensory evaluation in response to the stimulus was investigated using a visual analogue scale (VAS) and by interview. In many cases, the SEP amplitude and VAS value tended to decrease when illuminance was lowered and tended to increase when illuminance was raised. However, in a few cases, SEP amplitude and VAS value tended to increase in spite of the low illuminance. The occurrence of attention responses and unpleasant emotional responses caused by lowering the illuminance seems to be related to this study finding.

To investigate the role of the medial parietal region (MPR), comprising area 7 m and the retrosplenial and posterior cingulate cortices, in spatial navigation, we analyzed the spatial aspect of the responses of the MPR neurons in monkeys while they actively performed a navigation task in a virtual environment. One-third of the analyzed MPR neurons were activated depending on the location of the monkeys in the environment, that is, showed place-selective responses. Some neurons showed varying responses based on the starting point (SP) or destination. We further investigated the responses of the place-selective neurons when the monkeys were shown animations of the entire navigation route, including the preferred field, and a segment of the route, including an area around the preferred field, and a still image of the preferred field. We observed that the responses of some place-selective neurons reduced when the monkeys viewed the preferred field in the segmented animation or in the still image compared with when they viewed the entire animation. These results suggested that the knowledge about the SP or destination, that is, context, is necessary to activate place-selective neurons. The effect of such contextual information suggests that the MPR plays decisive roles in spatial processing such as navigation.

To examine the neural basis of route knowledge by which one can reach one's destination, we recorded the activity of 580 neurons in the monkey medial parietal region (MPR) while monkeys actively navigated through a virtual environment. One hundred eighty of these neurons (31%) showed significant responses to the monkeys' movements in the virtual environment. Of these responsive neurons, 77% (139/180) showed responses associated with a specific movement at a specific location (navigation neurons), 8% (14/180) showed responses associated with a specific movement (movement-selective neurons), and the remaining 27 neurons (15%) were nonselective. We found navigation neurons whose responses to the same movement at the same location were modulated depending on the route that the monkey was currently taking, that is, in a route-selective manner (32 of 59 tested neurons among 139 navigation neurons, route-selective navigation neurons). The reversible inactivation of MPR neurons by muscimol resulted in a monkey becoming lost during the navigation task trial. These results suggest that MPR plays a critical role in route-based navigation by integrating location information and self-movement information.

Anterior cingulate cortex is important in monitoring action for new challenges. We recorded neuron activity in the anterior cingulate sulcus of macaques while they performed a sequential problem-solving task. By trial and error, animals determined the correct sequence for touching three fixed spatial targets. After the sequence was repeated three times, we then changed the correct solution order, requiring a new search. Irrespective of component movements or their kinematics, task-related neurons encoded the serial order of the sequence. Neurons activated with sequence components (68%) differed in activity between search and repetition. Search-related activity occurred when behavioral flexibility was required and ended as soon as the animal accumulated enough information to infer the solution, but had not yet tested it. Repetition-related activity occurred in a regime of memory-based motor performance in which attention to action is less necessary.