http://www.cell.com/article/S0092867422000770/pdf

Structural and functional characterizations of infectivity and immune evasion of SARS-CoV-2 Omicron

Phase Separation in Genome Organization across Evolution

The COVID-19 pandemic caused by the SARS-CoV-2 virus has resulted in an unprecedented public health crisis. There are no approved vaccines or therapeutics for treating COVID-19. Here we reported a humanized monoclonal antibody, H014, efficiently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 at nM level by engaging the S receptor binding domain (RBD). Importantly, H014 administration reduced SARS-CoV-2 replication and prevented pulmonary pathology in hACE2 mouse model. Cryo-EM characterization of the SARS-CoV-2 S trimer in complex with the H014 Fab fragment unveiled a novel conformational epitope, which is only accessible when the RBD is in open conformation. Biochemical, cellular, virological and structural studies demonstrated that H014 prevents attachment of SARS-CoV-2 to its host cell receptors. Epitope analysis of available neutralizing antibodies against SARS-CoV and SARS-CoV-2 uncover broad cross-protective epitopes. Our results highlight a key role for antibody-based therapeutic interventions in the treatment of COVID-19. One sentence summary A potent neutralizing antibody conferred protection against SARS-CoV-2 in an hACE2 humanized mouse model by sterically blocking the interaction of the virus with its receptor.

https://biorxiv.org/content/10.1101/2020.06.02.129098v1.full.pdf

Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody

The genome packaging motor of bacteriophages and herpesviruses is built by two terminase subunits, known as large (TerL) and small (TerS), both essential for viral genome packaging. TerL structure, composition, and assembly to an empty capsid, as well as the mechanisms of ATP-dependent DNA packaging, have been studied in depth, shedding light on the chemo-mechanical coupling between ATP hydrolysis and DNA translocation. Instead, significantly less is known about the small terminase subunit, TerS, which is dispensable or even inhibitory in vitro, but essential in vivo. By taking advantage of the recent revolution in cryo-electron microscopy (cryo-EM) and building upon a wealth of crystallographic structures of phage TerSs, in this review, we take an inventory of known TerSs studied to date. Our analysis suggests that TerS evolved and diversified into a flexible molecular framework that can conserve biological function with minimal sequence and quaternary structure conservation to fit different packaging strategies and environmental conditions.

https://www.mdpi.com/1999-4915/14/10/2215/pdf?version=1666767753

Viral Small Terminase: A Divergent Structural Framework for a Conserved Biological Function

The packaging of DNA into preformed capsids is a critical step during herpesvirus infection. For herpes simplex virus, this process requires the products of seven viral genes: the terminase proteins pUL15, pUL28, and pUL33; the capsid vertex-specific component (CVSC) proteins pUL17 and pUL25; and the portal proteins pUL6 and pUL32. The pUL6 portal dodecamer is anchored at one vertex of the capsid by interactions with the adjacent triplexes as well as helical density attributed to the pUL17 and pUL25 subunits of the CVSC. To define the roles and structures of the CVSC proteins in virus assembly and DNA packaging, we isolated a number of recombinant viruses expressing pUL25, pUL17, and pUL36 fused with green or red fluorescent proteins as well as viruses with specific deletions in the CVSC genes. Biochemical and structural studies of these mutants demonstrated that (i) four of the helices in the CVSC helix bundle can be attributed to two copies each of pUL36 and pUL25, (ii) pUL17 and pUL6 are required for capsid binding of the terminase complex in the nucleus, (iii) pUL17 is important for determining the site of the first cleavage reaction generating replicated genomes with termini derived from the long-arm component of the herpes simplex virus 1 (HSV-1) genome, (iv) pUL36 serves no direct role in cleavage/packaging, (v) cleavage and stable packaging of the viral genome involve an ordered interaction of the terminase complex and pUL25 with pUL17 at the portal vertex, and (vi) packaging of the viral genome results in a dramatic displacement of the portal.IMPORTANCE Herpes simplex virus 1 (HSV-1) is the causative agent of several pathologies ranging in severity from the common cold sore to life-threatening encephalitic infection. A critical step during productive HSV-1 infection is the cleavage and packaging of replicated, concatemeric viral DNA into preformed capsids. A key knowledge gap is how the capsid engages the replicated viral genome and the subsequent packaging of a unit-length HSV genome. Here, biochemical and structural studies focused on the unique portal vertex of wild-type HSV and packaging mutants provide insights into the mechanism of HSV genome packaging. The significance of our research is in identifying the portal proteins pUL6 and pUL17 as key viral factors for engaging the terminase complex with the capsid and the subsequent cleavage, packaging, and stable incorporation of the viral genome in the HSV-1 capsid.

Role of the Herpes Simplex Virus CVSC Proteins at the Capsid Portal Vertex.

With the wide use of NVM-based DNN accelerators for higher computing efficiency, the long data retention time essentially causes a high risk of unauthorized weight stealing by attackers. Weight encryption is an effective method, but existing ciphertext computing accelerators cannot achieve high encryption complexity and flexibility. This paper proposes WeightLock, a mixed-grained hardware-software co-design approach based on local decrypting units (LDUs). This work proposes a key-controlled cell-level hardware design for higher granularity and two weight selection schemes for higher flexibility. The simulation results show that the accuracy of VGG-8 and ResNet-18 in the Cifar-10 classification drops from 80% to only 10% even if 80% of keys are leaked. This shows >20% higher key leakage tolerance and >17x longer retraining latency protection, compared with the prior state-of-the-art hardware and software approaches, respectively. The area cost of the encryption function is negligible, with ~600x, 2.2x, and 2.4x reduction from the state-of-the-art cell-wise, column-wise, and 1T4R structures, respectively.

WeightLock: A Mixed-Grained Weight Encryption Approach Using Local Decrypting Units for Ciphertext Computing in DNN Accelerators

Intellectual property (IP) piracy has become a nonnegligible problem as the integrated circuit (IC) production supply chain is becoming increasingly globalized and separated that enables attacks by potentially untrusted attackers. Logic locking is a widely adopted method to lock the circuit module with a key and prevent hackers from cracking it. The key is the critical aspect of logic locking, but the existing works have overlooked three possible challenges of the key: safety of key storage, easy keyattempt from interface and key-related overheads, bringing the further challenges of low error rate and small state space. In this work, the key is dynamically generated by utilizing the huge space of a CPU core, and the unlocking is performed implicitly through the interconnection inside the chip. A novel low-cost logic reconfigurable gate is together proposed with ferroelectric FET (FeFET) to mitigate the reverse engineering and removal attack. Compared to the common logic locking methods, our proposed approach is 19,945 times more time consuming to traverse all the possible combinations in only 9-bit-key condition. Furthermore, our technique let key length increases this complexity exponentially and ensure the logic obfuscation effect.

ALL-MASK: A Reconfigurable Logic Locking Method for Multicore Architecture with Sequential-Instruction-Oriented Key

Genome sequence analysis is a powerful tool in medical and scientific research. Considering the inevitable sequencing errors and genetic variations, approximate string matching (ASM) has been adopted in practice for genome sequencing. However, with exponentially increasing bio-data, ASM hardware acceleration is facing severe challenges in improving the throughput and energy efficiency with the accuracy constraint. This paper presents ASMCap, an ASM acceleration approach for genome sequence analysis with hardware-algorithm co-optimization. At the circuit level, ASMCap adopts charge-domain computing based on the capacitive multi-level content addressable memories (ML-CAMs), and outperforms the state-of-the-art ML-CAM-based ASM accelerators EDAM with higher accuracy and energy efficiency. ASMCap also has misjudgment correction capability with two proposed hardware-friendly strategies, namely the Hamming-Distance Aid Correction (HDAC) for the substitution-dominant edits and the Threshold-Aware Sequence Rotation (TASR) for the consecutive indels. Evaluation results show that ASMCap can achieve an average of 1.2x (from 74.7% to 87.6%) and up to 1.8x (from 46.3% to 81.2%) higher F1 score (the key metric of accuracy), 1.4x speedup, and 10.8x energy efficiency improvement compared with EDAM. Compared with the other ASM accelerators, including ResMA based on the comparison matrix, and SaVI based on the seeding strategy, ASMCap achieves an average improvement of 174x and 61x speedup, and 8.7e3x and 943x higher energy efficiency, respectively.

pdf/asmcap-an-approximate-string-matching-accelerator-for-genome-1lzei7qr.pdf

ASMCap: An Approximate String Matching Accelerator for Genome Sequence Analysis Based on Capacitive Content Addressable Memory

Genome packaging is a fundamental process in a viral life cycle and a prime target of antiviral drugs. Herpesviruses use an ATP-driven packaging motor/terminase complex to translocate and cleave concatemeric dsDNA into procapsids but its molecular architecture and mechanism are unknown. We report atomic structures of a herpesvirus hexameric terminase complex in both the apo and ADP•BeF3-bound states. Each subunit of the hexameric ring comprises three components-the ATPase/terminase pUL15 and two regulator/fixer proteins, pUL28 and pUL33-unlike bacteriophage terminases. Distal to the nuclease domains, six ATPase domains form a central channel with conserved basic-patches conducive to DNA binding and trans-acting arginine fingers are essential to ATP hydrolysis and sequential DNA translocation. Rearrangement of the nuclease domains mediated by regulatory domains converts DNA translocation mode to cleavage mode. Our structures favor a sequential revolution model for DNA translocation and suggest mechanisms for concerted domain rearrangements leading to DNA cleavage.

/pdf/architecture-of-the-herpesvirus-genome-packaging-complex-and-41n6026r3k.pdf

Architecture of the herpesvirus genome-packaging complex and implications for DNA translocation

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WeightLock: A Mixed-Grained Weight Encryption Approach Using Local Decrypting Units for Ciphertext Computing in DNN Accelerators

ALL-MASK: A Reconfigurable Logic Locking Method for Multicore Architecture with Sequential-Instruction-Oriented Key

ASMCap: An Approximate String Matching Accelerator for Genome Sequence Analysis Based on Capacitive Content Addressable Memory

Architecture of the herpesvirus genome-packaging complex and implications for DNA translocation