Expression of stm4467-encoded arginine deiminase controlled by the stm4463 regulator contributes to salmonella enterica serovar typhimurium virulence

Arginine deiminase (ADI), carbamate kinase (CK), and ornithine transcarbamoylase (OTC) constitute the ADI system. In addition to metabolic functions, the ADI system has been implicated in the virulence of certain pathogens. The pathogenic intracellular bacterium Salmonella enterica serovar Typhimurium possesses the STM4467, STM4466, and STM4465 genes, which are predicted to encode ADI, CK, and OTC, respectively. Here we report that the STM4467 gene encodes an ADI and that ADI activity plays a role in the successful infection of a mammalian host by S. Typhimurium. An STM4467 deletion mutant was defective for replication inside murine macrophages and was attenuated for virulence in mice. We determined that a regulatory protein encoded by the STM4463 gene functions as an activator for STM4467 expression. The expression of the ADI pathway genes was enhanced inside macrophages in a process that required STM4463. Lack of STM4463 impaired the ability of S. Typhimurium to replicate within macrophages. A mutant defective in STM4467-encoded ADI displayed normal production of nitric oxide by macrophages

Efficient Sorting of Homomorphic Encrypted Data with kk-way Sorting Network

In this study, we propose an efficient sorting method for encrypted data using fully homomorphic encryption (FHE). The proposed method extends the existing 2-way sorting method by applying the $k$-way sorting network for any prime $k$ to reduce the depth in terms of comparison operation from $O(\log_2^2 n)$ to $O(k\log_k^2 n)$, thereby improving performance for $k$ slightly larger than $2$, such as $k=5$. We apply this method to approximate FHE which is widely used due to its efficiency of homomorphic arithmetic operations. In order to build up the $k$-way sorting network, the $k$-sorter, which sorts $k$-numbers with a minimal comparison depth, is used as a building block. The approximate homomorphic comparison, which is the only type of comparison working on approximate FHE, cannot be used for the construction of the $k$-sorter as it is because the result of the comparison is not binary, unlike the comparison in conventional bit-wise FHEs. To overcome this problem, we propose an efficient $k$-sorter construction utilizing the features of approximate homomorphic comparison. Also, we propose an efficient construction of a $k$-way sorting network using cryptographic SIMD operations. To use the proposed method most efficiently, we propose an estimation formula that finds the appropriate $k$ that is expected to reduce the total time cost when the parameters of the approximating comparisons and the performance of the operations provided by the approximate FHE are given. We also show the implementation results of the proposed method, and it shows that sorting $5^6=15625$ data using $5$-way sorting network can be about $23.3\%$ faster than sorting $2^{14}=16384$ data using $2$-way

Cross-genotype protection of live-attenuated vaccine candidate for severe fever with thrombocytopenia syndrome virus in a ferret model

Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) is an emerging tick-borne virus classified within the Banyangvirus genus. SFTS disease has been reported throughout East Asia since 2009 and is characterized by high fever, thrombocytopenia, and leukopenia and has a 12 to 30% case fatality rate. Due to the recent emergence of SFTSV, there has been little time to conduct research into preventative measures aimed at combatting the virus. SFTSV is listed as one of the World Health Organization’s Prioritized Pathogens for research into antiviral therapeutics and vaccine development. Here, we report 2 attenuated recombinant SFTS viruses that induce a humoral immune response in immunized ferrets and confer complete cross-genotype protection to lethal challenge. Animals infected with rHB29NSsP102A or rHB2912aaNSs (both genotype D) had a reduced viral load in both serum and tissues and presented without high fever, thrombocytopenia, or mortality associated with infection. rHB29NSsP102A- or rHB2912aaNSs-immunized animals developed a robust anti-SFTSV immune response against cross-genotype isolates of SFTSV. This immune response was capable of neutralizing live virus in a focus-reduction neutralization test (FRNT) and was 100% protective against a cross-genotype lethal challenge with the CB1/2014 strain of SFTSV (genotype B). Thus, using our midsized, aged ferret infection model, we demonstrate 2 live attenuated vaccine candidates against the emerging pathogen SFTSV

The cap-snatching SFTSV endonuclease domain is an antiviral target

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne virus with 12%-30% case mortality rates and is related to the Heartland virus (HRTV) identified in the United States. Together, SFTSV and HRTV are emerging segmented, negative-sense RNA viral (sNSV) pathogens with potential global health impact. Here, we characterize the amino-terminal cap-snatching endonuclease domain of SFTSV polymerase (L) and solve a 2.4-Å X-ray crystal structure. While the overall structure is similar to those of other cap-snatching sNSV endonucleases, differences near the C terminus of the SFTSV endonuclease suggest divergence in regulation. Influenza virus endonuclease inhibitors, including the US Food and Drug Administration (FDA) approved Baloxavir (BXA), inhibit the endonuclease activity in in vitro enzymatic assays and in cell-based studies. BXA displays potent activity with a half maximal inhibitory concentration (I

Severe fever with thrombocytopenia syndrome phlebovirus non-structural protein activates TPL2 signalling pathway for viral immunopathogenesis

Severe fever with thrombocytopenia syndrome phlebovirus (SFTSV), listed in the World Health Organization Prioritized Pathogens, is an emerging phlebovirus with a high fatality . Owing to the lack of therapies and vaccines , there is a pressing need to understand SFTSV pathogenesis. SFSTV non-structural protein (NSs) has been shown to block type I interferon induction and facilitate disease progression . Here, we report that SFTSV-NSs targets the tumour progression locus 2 (TPL2)-A20-binding inhibitor of NF-κB activation 2 (ABIN2)-p105 complex to induce the expression of interleukin-10 (IL-10) for viral pathogenesis. Using a combination of reverse genetics, a TPL2 kinase inhibitor and Tpl2 mice showed that NSs interacted with ABIN2 and promoted TPL2 complex formation and signalling activity, resulting in the marked upregulation of Il10 expression. Whereas SFTSV infection of wild-type mice led to rapid weight loss and death, Tpl2 mice or Il10 mice survived an infection. Furthermore, SFTSV-NSs P A and SFTSV-NSs K R that lost the ability to induce TPL2 signalling and IL-10 production showed drastically reduced pathogenesis. Remarkably, the exogenous administration of recombinant IL-10 effectively rescued the attenuated pathogenic activity of SFTSV-NSs P A, resulting in a lethal infection. Our study demonstrates that SFTSV-NSs targets the TPL2 signalling pathway to induce immune-suppressive IL-10 cytokine production as a means to dampen the host defence and promote viral pathogenesis

TRIM9-Mediated Resolution of Neuroinflammation Confers Neuroprotection upon Ischemic Stroke in Mice

Excessive and unresolved neuroinflammation is a key component of the pathological cascade in brain injuries such as ischemic stroke. Here, we report that TRIM9, a brain-specific tripartite motif (TRIM) protein, was highly expressed in the peri-infarct areas shortly after ischemic insults in mice, but expression was decreased in aged mice, which are known to have increased neuroinflammation after stroke. Mechanistically, TRIM9 sequestered β-transducin repeat-containing protein (β-TrCP) from the Skp-Cullin-F-box ubiquitin ligase complex, blocking IκBα degradation and thereby dampening nuclear factor κB (NF-κB)-dependent proinflammatory mediator production and immune cell infiltration to limit neuroinflammation. Consequently, Trim9-deficient mice were highly vulnerable to ischemia, manifesting uncontrolled neuroinflammation and exacerbated neuropathological outcomes. Systemic administration of a recombinant TRIM9 adeno-associated virus that drove brain-wide TRIM9 expression effectively resolved neuroinflammation and alleviated neuronal death, especially in aged mice. These findings reveal that TRIM9 is essential for resolving NF-κB-dependent neuroinflammation to promote recovery and repair after brain injury and may represent an attractive therapeutic target

Approximating Max Function in Fully Homomorphic Encryption

This study focuses on efficiently finding the location of the maximum value for large-scale values encrypted by the CKKS (Cheon—Kim—Kim–Song) method. To find the maximum value, logM+1 comparison operations and logM rotation operations, and 2logM+3 additions and 2logM+1 multiplications are required. However, there is no known way to find a k-approximate maximum value, i.e., a value with the same most significant k-bits as the maximum value. In this study, when the value range of all data in each slot in the ciphertext is [0, 1], we propose a method for finding all slot positions of values whose most significant k-bits match the maximum value. The proposed method can find all slots from the input ciphertexts where their values have the same most significant k-bits as the maximum value by performing 2k comparison operations, (4k+2) multiplications, (6k+2klogM+3) additions, and 2klogM rotation operations. Through experiments and complexity analysis, we show that the proposed method is more efficient than the existing method of finding all locations where the k MSB is equal to the maximum value. The result of this can be applied to various privacy-preserving applications in various environments, such as IoT devices

A Study on the Interoperability Technology of Digital Identification Based on WACI Protocol with Multiparty Distributed Signature

In digital identity authentication, credentials are typically stored in a digital wallet and authenticated through a single key-based signature and public key verification. However, ensuring compatibility between systems and credentials can be challenging and the existing architecture can create a single point of failure, which can hinder system stability and prevent data interchange. To address this problem, we propose a multiparty distributed signature structure using FROST, a Schnorr signature-based threshold signature algorithm, applied to the WACI protocol framework for credential interaction. This approach eliminates a single point of failure and secures the signer’s anonymity. Additionally, by following standard interoperability protocol procedures, we can ensure interoperability during the exchange of digital wallets and credentials. This paper presents a method that combines a multiparty distributed signature algorithm and an interoperability protocol, and discusses the implementation results