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The role of prokaryotic CRISPR/Cas system proteins as a defensive shield against invasive nucleic acids has been studied extensively. Non-canonical roles in pathogenesis involving intracellular targeting of certain virulence-associated endogenous mRNA have also been reported for some Type I and Type II CRISPR/Cas proteins, but no such roles have yet been established for Type III system proteins. Here, we demonstrate that M. tuberculosis (Type III-A system) CRISPR/Cas proteins Csm1, Csm3, Csm5, Csm6, and Cas6 are secreted and induce host immune responses. Using cell and animal experiments, we show that Cas6, in particular, provokes IFN-γ release from PBMCs from active tuberculosis (TB) patients, and its deletion markedly attenuates virulence in a murine M. tuberculosis challenge model. Recombinant MTBCas6 induces apoptosis of macrophages and lung fibroblasts, and interacts with the surface of cells in a caspase and TLR-2 independent manner. Transcriptomic and signal pathway studies using THP-1 macrophages stimulated with MTBCas6 indicated that MTBCas6 upregulates expression of genes associated with the NF-κB pathway leading to higher levels of IL-6, IL-1β, and TNF-α release, cytokines known to activate immune system cells in response to M. tuberculosis infection. Our findings suggest that, in addition to their intracellular shielding role, M. tuberculosis CRISPR/Cas proteins have non-canonical extracellular roles, functioning like a virulent sword, and activating host immune responses.

The present tectonic regime of the Qilian Shan is dominated by large northeast and northwest striking strike‐slip faults and northwest striking thrust faults. Deformation distribution between the subparallel Haiyuan Strike‐slip Fault and the Minle‐Damaying Thrust Fault (MDF) is crucial for understanding the orogenic mechanism of the northeastern Tibetan Plateau. However, the uncertain kinematics of the MDF and the stress variation along the strike‐varying Haiyuan Fault inhibit further discussion of their relationship. Five key sites along the MDF were selected for analysis of terrace abandonment ages and vertical offsets to determine the slip rates. Two finite element models were constructed to calculate the stress‐strain relationship between the Haiyuan Fault and MDF. We find that the activity of the MDF can be divided into two segments by a stepover with less activity and lower terrain at the Xida River site. Shortening rates of the MDF vary between 0.2 and 2.4 mm/a since the late Pleistocene with trapezoidal trends on both fault segments. The two finite element models and GPS data reveal that the strain rates are lower at the Xida River site but higher at the Menyuan Bend on the Haiyuan Fault. We infer that long‐term strain accumulation at the Menyuan Bend may have mitigated the tectonic activity northeast to the bend under the northeastward stress field, including the activity of the MDF at the Xida River site, and resulted in the segmentation of the MDF. Plain Language Summary: The Haiyuan strike‐slip fault and the Minle‐Damaying thrust fault (MDF) are two important parallel faults that help us understand the growth of the Qilian Shan. The influence of multiple bends of the Haiyuan fault on the activities of its adjacent faults has not been clearly studied. Therefore, we investigated in detail the terraces of five rivers that were offset by the MDF, and determined the spatial variation of the MDF activity rates based on the vertical separations and abandonment ages of the terraces. We also established two finite element models showing the deformation distribution between the Haiyuan Fault and MDF on the upper crustal and crustal scales, respectively. We have found that the Menyuan Bend of the Haiyuan Fault absorbs a significant amount of shortening deformation under the regional northeastward stress field and probably causes the very low activity rate of the MDF at the Xida River site in the northeast of the bend, in contrast to the obvious higher activity rates on both sides of the site, indicating that the activity of the MDF is segmented at the Xida River. The relationship and seismic risk between the two faults are worthy of continuous attention. Key Points: The slip rates of the Minle‐Damaying Thrust Fault (MDF) show its segmentation at stepover near the Xida River with trapezoidal variation trends on both segmentsThe strain rate is lower at the Xida River site but higher at the Menyuan Bend on the Haiyuan FaultStrain accumulation at the Menyuan Bend has reduced the activity of the MDF at the Xida River site [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (MTB) infection, remains a major threat to global public health. To facilitate early TB diagnosis, an IS6110 gene-based recombinase aided amplification (RAA) assay was coupled to a clustered, regularly interspaced short palindromic repeats (CRISPR)-Cas13a fluorescence assay to create a rapid MTB detection assay (named RAA-CRISPR-MTB). Its diagnostic efficacy was evaluated for sensitivity and specificity through sequential testing of recombinant plasmids, mycobacterium strains, and clinical specimens. RAA-CRISPR detected IS6110 genes at levels approaching 1 copy/μL with pUC57-6110 as the template and 10 copies/μL with H37Rv as the template. There was no observed cross detection of non-tuberculosis mycobacteria (NTM) with either template. Furthermore, RAA-CRISPR testing of 151 clinical specimens yielded a diagnostic specificity rate of 100% and a diagnostic sensitivity rate of 69% that exceeded the corresponding Xpert MTB/RIF assay rate (60%). In conclusion, we established a novel RAA-CRISPR assay that achieved highly sensitive and specific MTB detection for use as a clinical TB diagnostic tool in resource-poor settings. [ABSTRACT FROM AUTHOR]

The Ganzi–Xianshuihe Fault Zone is a large-scale sinistral strike-slip fault zone on the eastern Tibet. As the boundary fault zone of the Bayankala Block and the Chuandian Block, it controls the clockwise rotation of the southeastern Tibet. However, there is still controversy regarding the activity changes between fault zones. Therefore, accurately determining the slip rates of faults in the area is crucial for characterizing regional plate motions and assessing associated seismic hazards. We focused on studying four fault segments near the Ganzi–Xianshuihe Fault Zone, including the Manigango, Ganzi, Luhuo, and Daofu segments. In each segment, we selected typical sinistral piercing points and carried out Unmanned Aerial Vehicle (UAV) photogrammetry to obtain high-resolution terrain data. We utilized LaDiCaoz_V2.2 and GlobalMapper software (LaDiCaoz_V2.2 and Global Mapper v17.0) to measure the offsets, together with optically stimulated luminescence (OSL) dating, to constrain the timing of fault activity. The estimated slip rates for the Manigango, Ganzi, Luhuo, and Daofu segments are as follows: 9.2 ± 0.75 mm/yr, 9.59 ± 1.7 mm/yr, 4.23 ± 0.66 mm/yr, and 7.69 ± 0.76 mm/yr, respectively. Integrating previous results with slip rates estimated in this study, our analysis suggests the slip rate of the Ganzi–Xianshuihe Fault Zone is around 8–10 mm/year, exhibiting a consistent slip rate from northwest to southeast. This reflects the overall coordination of the movement on the eastern Tibet, with the strike-slip fault zone only controlling the direction of movement. [ABSTRACT FROM AUTHOR]

Summary: Convolutional neural networks (CNNs) have shown remarkable advantages in a wide range of domains at the expense of huge parameters and computations. Modern CNNs still tend to be more complex and larger to achieve better inference accuracy. However, the complex and large structures of CNNs could slow down the inference speed. Recently, Compressing the convolutional weights to be sparse by pruning the unimportant parameters has been demonstrated as an efficient way to reduce the computations of CNNs. On the other hand, field‐programmable gate arrays (FPGAs) have been a popular hardware platform to accelerate CNN inference. In this paper, we propose an algorithm/hardware co‐optimized method for accelerating CNN inference on FPGAs. For the algorithm, we take advantage of unstructured and structured parameter sparsifying methods to achieve high sparsity and keep the regularity of convolutional weights. Correspondingly, hardware‐friendly index representations of sparse convolutional weights are proposed. For the hardware architecture, we propose row‐wise input‐stationary dataflow, which is tightly coupled with the algorithm. A row‐wise computing engine (RConv Engine) is proposed, which is based on the dataflow. Inside the RConv Engine, the scalar‐vector structure is applied to implement the basic processing elements (PEs). To flexibly calculate the feature map with various sizes, the PEs are organized in a 2D structure with two work modes. The experimental results demonstrate that our co‐optimized method implements high sparsity of convolutional weights, and the computing engine achieves high computation efficiency. Compared with other accelerators, our co‐optimized method implements a 10.9×$$ \times $$ speedup on FPS at most with the highest sparsity of convolutional weights and negligible accuracy loss. [ABSTRACT FROM AUTHOR]

The Tieluzi Fault is the largest structure in the East Qinling Mountains, and is considered to be the easternmost continuation of the Altyn Tagh‐Haiyuan‐Qinling Fault System (AHQFS) that allows the eastward extrusion of the Tibetan Plateau and South China Block. We studied the fault geometry and kinematics of the Tieluzi Fault using field investigations, detailed interpretations of high‐resolution satellite imagery and digital elevation models, and late Quaternary dating methods. Paleoseismic investigations indicate that the most recent earthquake along the Tieluzi Fault occurred before 1,500–1,300 cal. BP. Geological and geomorphological observations show that segments west of Lushi County are more active than those to the east. The spatial variations in tectonic activity along the Tieluzi Fault are interpreted to be related to four possible mechanisms: strike change, discontinuity, intersection, and branch. The late Quaternary left‐lateral slip rate is determined to be 0.9 ± 0.1 mm/yr on the Tieluzi Fault. The prominent left‐lateral faulting along the Tieluzi Fault suggests that most of the left‐lateral displacement along the eastern AHQFS has been accommodated by the Tieluzi Fault, which forms the most frontier of the eastward expansion of the Tibetan Plateau. Furthermore, we suggest that the left‐lateral faulting in the East Qinling Mountains is a response to relative eastward motion of the South China block pushed by the Tibetan Plateau with respect to the North China Plain Block. Also, our results indicate that the Tibetan Plateau has undergone a stepwise eastward expansion. Key Points: Paleoseismic investigations indicate that the most recent earthquake along the Tieluzi Fault occurred before 1,500–1,300 cal. BPThe late Quaternary left‐lateral slip rate is determined to be 0.9 ± 0.1 mm/yr on the Tieluzi FaultThe prominent left‐lateral faulting along the Tieluzi Fault is a far‐field response for the eastward expansion of the Tibetan Plateau [ABSTRACT FROM AUTHOR]