Discovery of N-Benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine as a Potential Antifungal Agent against Sporidia Growth and Teliospore Germination of Sporisorium scitamineum.

The cultivation of sugar cane using perennial roots is the primary planting method, which is one of the reasons for the serious occurrence of sugar cane smut disease caused by the basidiomycetous fungus Sporisorium scitamineum in the sugar cane perennial root planting area. Consequently, it is crucial to eliminate pathogens from perennial sugar cane buds. In this study, we found that MAP kinase Hog1 is necessary for heat stress resistance. Subsequent investigations revealed a significant reduction in the expression of the heat shock protein 104-encoding gene, SsHSP104, in the ss1hog1Δ mutant. Additionally, the overexpression of SsHSP104 partially restored colony growth in the ss1hog1Δ strain following heat stress treatment, demonstrating the crucial role of SsHsp104 in SsHog1-mediated heat stress tolerance. Hence, we constructed the ss1hsp104:eGFP fusion strain in the wild type of S. scitamineum to identify small-molecule compounds that could inhibit the heat stress response, leading to the discovery of N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine as a potential compound that targets the SsHog1 mediation SsHsp104 pathway during heat treatment. Furthermore, the combination of N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine and warm water treatment (45 °C for 15 min) inhibits the growth of S. scitamineum and teliospore germination, thereby reducing the occurrence of sugar cane smut diseases and indicating its potential for eliminating pathogens from perennial sugar cane buds. In conclusion, these findings suggest that N-benzyl-4-(1-bromonaphthalen-2-yl)oxybutan-1-amine is promising as a targeted compound for the SsHog1-mediated SsHsp104 pathway and may enable the reduction of hot water treatment duration and/or temperature, thereby limiting the occurrence of sugar cane smut diseases caused by S. scitamineum.

Cytochrome c-peroxidase modulates ROS homeostasis to regulate the sexual mating of Sporisorium scitamineum.

IMPORTANCE: Reactive oxygen species play an important role in pathogen-plant interactions. In fungi, cytochrome c-peroxidase maintains intracellular ROS homeostasis by utilizing H2O2 as an electron acceptor to oxidize ferrocytochrome c, thereby contributing to disease pathogenesis. In this study, our investigation reveals that the cytochrome c-peroxidase encoding gene, SsCCP1, not only plays a key role in resisting H2O2 toxicity but is also essential for the mating/filamentation and pathogenicity of S. scitamineum. We further uncover that SsCcp1 mediates the expression of SsPrf1 by maintaining intracellular ROS homeostasis to regulate S. scitamineum mating/filamentation. Our findings provide novel insights into how cytochrome c-peroxidase regulates sexual reproduction in phytopathogenic fungi, presenting a theoretical foundation for designing new disease control strategies.

Mammalian mitochondrial translation infidelity leads to oxidative stress-induced cell cycle arrest and cardiomyopathy.

Proofreading (editing) of mischarged tRNAs by cytoplasmic aminoacyl-tRNA synthetases (aaRSs), whose impairment causes neurodegeneration and cardiac diseases, is of high significance for protein homeostasis. However, whether mitochondrial translation needs fidelity and the significance of editing by mitochondrial aaRSs have been unclear. Here, we show that mammalian cells critically depended on the editing of mitochondrial threonyl-tRNA synthetase (mtThrRS, encoded by Tars2), disruption of which accumulated Ser-tRNAThr and generated a large abundance of Thr-to-Ser misincorporated peptides in vivo. Such infidelity impaired mitochondrial translation and oxidative phosphorylation, causing oxidative stress and cell cycle arrest in the G0/G1 phase. Notably, reactive oxygen species (ROS) scavenging by N-acetylcysteine attenuated this abnormal cell proliferation. A mouse model of heart-specific defective mtThrRS editing was established. Increased ROS levels, blocked cardiomyocyte proliferation, contractile dysfunction, dilated cardiomyopathy, and cardiac fibrosis were observed. Our results elucidate that mitochondria critically require a high level of translational accuracy at Thr codons and highlight the cellular dysfunctions and imbalance in tissue homeostasis caused by mitochondrial mistranslation.

Entanglement-Enhanced Magnetic Induction Tomography.

Magnetic induction tomography (MIT) is a sensing protocol exploring conductive objects via their response to radio-frequency magnetic fields. MIT is used in nondestructive testing ranging from geophysics to medical applications. Atomic magnetometers, employed as MIT sensors, allow for significant improvement of the MIT sensitivity and for exploring its quantum limits. Here, we propose and verify a quantum-enhanced version of the atomic MIT by combining it with conditional spin squeezing and stroboscopic backaction evasion. We use this quantum enhancement to demonstrate sensitivity beyond the standard quantum limits of one-dimensional quantum MIT detecting a conductive sample.

Improvement in the performance of an autoantibody panel in combination with heat shock protein 90a for the detection of early­stage lung cancer.

The early diagnosis of lung cancer is closely associated with the decline of mortality. A panel consisting of seven lung cancer-related autoantibodies (7-AABs) has been shown to be a reliable and specific indicator for the early detection of lung cancer, with a specificity of ~90% and a positive predictive value of ~85%. However, its low sensitivity and negative predictive value limit its wide application. To improve its diagnostic value, the diagnostic efficiencies of 7-AABs in combination with non-specific tumor markers were retrospectively investigated for the detection of early-stage lung cancer. A total of 217 patients with small lung nodules who presented with ground-glass opacity or solid nodules as well as 30 healthy controls were studied. The concentrations of 7-AABs and heat shock protein 90a (HSP90a) were assessed using ELISA. Automated flow fluorescence immune analysis was used for the assessment of CEA, CYFRA21-1, CA199 and CA125 levels. The results showed that 7-AABs + HSP90a possessed a remarkably improved diagnostic efficiency for patients with small pulmonary nodules or for patients with lung nodules of different types, which suggested that 7-AABs in combination with HSP90a could have a high clinical value for the improvement of the diagnostic efficiency of early-stage lung cancer.

Combination of Circulating Cell-Free DNA and Positron Emission Tomography to Distinguish Non-Small Cell Lung Cancer from Tuberculosis.

OBJECTIVE: Non-small cell lung cancer (NSCLC) holds high metabolic tumor burden and circulating cell-free DNA (cfDNA) levels, and the relationship between metabolic tumor burden and cfDNA in NSCLC and the underlying mechanism of their interaction therein remain poorly characterized. Our aim was to evaluate the clinical value of cfDNA and metabolic tumor burden by positron emission tomography-computed tomography (PET/CT) for NSCLC differential diagnosis from tuberculosis in patients with solitary pulmonary nodules. METHODS: Metabolic tumor burden values in humans (subjects with NSCLC, subjects with tuberculosis, and healthy control subjects) and relevant mouse models were detected by preoperative 18F-fluorodeoxyglucose PET (18F-FDG PET/CT) and [3H]-2-deoxy-DG uptake, respectively. The cfDNA levels were detected by quantifying serum cfDNA fragments from the ALU (115 bp) gene using reverse transcription-polymerase chain reaction. RNA sequence was performed to determine the underlying target genes and knocked down or inhibited the target genes in vivo and in vitro to determine the mechanism therein. RESULTS: Metabolic tumor burden correlated with serum cfDNA levels in NSCLC subjects but not in tuberculosis subjects or healthy controls. Mouse models showed a similar phenomenon. In addition, the RNA sequence showed that glucose transporter 1 (GLU1), factor-related apoptosis ligand (FasL), caspase 8, and caspase 3 were significantly increased in NSCLC mouse tumors compared with those in tuberculosis mouse masses. Inhibiting the metabolic tumor burden by blocking or knocking down GLU1 markedly reduced the expression of FasL, the phosphorylation of caspase 8/caspase 3, and serum cfDNA levels/apoptosis percentage in vivo and in vitro. Furthermore, the use of a combination of cfDNA and metabolic tumor burden allowed better ability to distinguish NSCLC subjects from those with tuberculosis or healthy controls than either method used alone. CONCLUSION: Metabolic tumor burden promotes the formation of circulating cfDNA through GLU1-mediated apoptosis in NSCLC, and the combination of cfDNA and metabolic tumor burden could be valuable for distinguishing NSCLC from tuberculosis.

Polarization beam splitting in a Glan-Taylor prism based on dual effects of both birefringence and Goos-Hanchen shift.

With the structure of biprism, polarization beam splitting in a Glan-Taylor polarizer was explored based on the birefringence and Goos-Hanchen shift. Due to the birefringence of the light in calcite crystal, the extraordinary light worked as the position calibration. As for the ordinary light, the propagated direction tilted noticeably due to the refraction as well as Goos-Hanchen effect at the prism-air interface of in the air gap. The Snell's law and stationary-phase approach were utilized for the calculation of the beam splitting between the two orthogonal polarization elements. By choosing appropriate incident angle and initial polarization, remarkable beam splitting was realized. With this configuration, the resolution with a magnitude of 10 - 5 ° and 10 - 3 ° was achieved for the response of the incident angle and polarization detection respectively.

Selective degradation of tRNASer(AGY) is the primary driver for mitochondrial seryl-tRNA synthetase-related disease.

Mitochondrial translation is of high significance for cellular energy homeostasis. Aminoacyl-tRNA synthetases (aaRSs) are crucial translational components. Mitochondrial aaRS variants cause various human diseases. However, the pathogenesis of the vast majority of these diseases remains unknown. Here, we identified two novel SARS2 (encoding mitochondrial seryl-tRNA synthetase) variants that cause a multisystem disorder. c.654-14T > A mutation induced mRNA mis-splicing, generating a peptide insertion in the active site; c.1519dupC swapped a critical tRNA-binding motif in the C-terminus due to stop codon readthrough. Both mutants exhibited severely diminished tRNA binding and aminoacylation capacities. A marked reduction in mitochondrial tRNASer(AGY) was observed due to RNA degradation in patient-derived induced pluripotent stem cells (iPSCs), causing impaired translation and comprehensive mitochondrial function deficiencies. These impairments were efficiently rescued by wild-type SARS2 overexpression. Either mutation caused early embryonic fatality in mice. Heterozygous mice displayed reduced muscle tissue-specific levels of tRNASers. Our findings elucidated the biochemical and cellular consequences of impaired translation mediated by SARS2, suggesting that reduced abundance of tRNASer(AGY) is a key determinant for development of SARS2-related diseases.

Kinase Hog1 and Adr1 Opposingly Regulate Haploid Cell Morphology by Controlling Vacuole Size in Sporisorium scitamineum.

Morphogenesis is a strictly regulated efficient system in eukaryotes for adapting to environmental changes. However, the morphogenesis regulatory mechanism in smut fungi is not clear. This study reports a relationship between MAP kinase Hog1 and cAMP-dependent protein kinase A catalytic subunit (Adr1) for the morphological regulation in the sugarcane pathogen Sporisorium scitamineum. The results demonstrated that MAP kinase Hog1 and cAMP/PKA signaling pathways are essential for the morphological development of S. scitamineum. Interestingly, MAP kinase Hog1 and cAMP/PKA signaling pathways' defective mutants exhibit an opposite morphological phenotype. The morphology of cAMP/PKA defective mutants is recovered by deleting the SsHOG1 gene. However, MAP kinase Hog1 and cAMP-dependent protein kinase catalytic subunit Adr1 do not interfere with each other. Further investigations showed that kinase Hog1 and Adr1 antagonistically regulates the vacuolar size, which contributes to the cell size and determines the cellular elongation rates. Kinase Hog1 and Adr1 also antagonistically balanced the cell wall integrity and permeability. Taken together, kinase Hog1- and Adr1-based opposing morphogenesis regulation of S. scitamineum by controlling the vacuolar size and cell wall permeability is established during the study.

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease.

TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants-one nonsense variant and six missense variants-that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function.

Nitrosative stress inhibits aminoacylation and editing activities of mitochondrial threonyl-tRNA synthetase by S-nitrosation.

Structure and/or function of proteins are frequently affected by oxidative/nitrosative stress via posttranslational modifications. Aminoacyl-tRNA synthetases (aaRSs) constitute a class of ubiquitously expressed enzymes that control cellular protein homeostasis. Here, we found the activity of human mitochondrial (mt) threonyl-tRNA synthetase (hmtThrRS) is resistant to oxidative stress (H2O2) but profoundly sensitive to nitrosative stress (S-nitrosoglutathione, GSNO). Further study showed four Cys residues in hmtThrRS were modified by S-nitrosation upon GSNO treatment, and one residue was one of synthetic active sites. We analyzed the effect of modification at individual Cys residue on aminoacylation and editing activities of hmtThrRS in vitro and found that both activities were decreased. We further confirmed that S-nitrosation of mtThrRS could be readily detected in vivo in both human cells and various mouse tissues, and we systematically identified dozens of S-nitrosation-modified sites in most aaRSs, thus establishing both mitochondrial and cytoplasmic aaRS species with S-nitrosation ex vivo and in vivo, respectively. Interestingly, a decrease in the S-nitrosation modification level of mtThrRS was observed in a Huntington disease mouse model. Overall, our results establish, for the first time, a comprehensive S-nitrosation-modified aaRS network and a previously unknown mechanism on the basis of the inhibitory effect of S-nitrosation on hmtThrRS.

Vector magnetocardiography measurement with a compact elliptically polarized laser-pumped magnetometer.

We report on a practical approach to vector biomagnetism measurement with an optically pumped magnetometer for measuring total magnetic field intensity. Its application to vector magnetocardiography is experimentally demonstrated with a compact elliptically polarized laser-pumped M x atomic magnetometer (EPMx OPM). The approach is proved to be effective and able to provide more complete cardiac magnetic information. The cardiac magnetic vectors are displayed in three-dimensional space in the form of magnetic vector loops. The sensor configuration and the image processing method here are expected to form further values, especially for multi-channel vector biomagnetism measurement, clinical diagnosis, and field source reconstruction.

A report of clinical diagnosis and treatment of nine cases of coronavirus disease 2019.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has become an important public health issue in the world. More than 118 000 cases were confirmed around the world. The main clinical manifestations were respiratory symptoms and occasional gastrointestinal symptoms. However, there is no unified standard for the diagnosis and treatment of COVID-19. In the retrospective analysis, we report nine cases of COVID-19, describe the history of contact, clinical manifestations, the course of diagnosis and clinical treatment before, during and after treatment.

Elliptically polarized laser-pumped Mx magnetometer towards applications at room temperature.

An atomic magnetometer operated with elliptically polarized light is investigated theoretically and experimentally. To explore the potential of this magnetometric configuration, the analytical form of the outgoing signal is derived. Parameters that significantly influence the performance are optimized, which lead to a sensitivity of 300 fT/Hz at 45 ∘C with a 2×2×2 cm uncoated Rb vapor cell. It is remarkable that a sensitivity of 690 fT/Hz is achieved at room temperature of 24 ∘C, which is improved by an order of magnitude compared with the conventional Mx magnetometer under its own optimized condition. The elliptically polarized approach offers attractive features for developing compact, low-power magnetometers, which are available without heating the uncoated vapor cell.

Fast backward singular value decomposition (SVD) algorithm for magnetocardiographic signal reconstruction from pulsed atomic magnetometer data.

In a pulse pump Rb atomic magnetometer, the magnetic field is associated with the Larmor frequency of the free induction decay (FID) signal. The reconstruction of the magnetic field from the collected signal, thereby, is crucial for magnetocardiography. In this study, we propose a backward singular value decomposition (BSVD) method for fast reconstruction of a magnetocardiographic signal. Experiments on the simulated and real data were performed to estimate its potential advantages over previous approaches, such as the fast Fourier transform (FFT) method, the zero-crossing means (ZM) method, etc. The results show the high accuracy of the BSVD method compared with other methods. More importantly, the BSVD method requires less sampled data than other methods while ensuring the accuracy. With the help of it, the recording time can be greatly reduced from the initial 3.6m s to the present 0.6m s. Thus, the time resolution of the magnetocardiograph could reach 2m s which is equivalent to that of conventional electrocardiogragh. This will bring the atomic magnetocardiography more practicable in clinic application.

The G3-U70-independent tRNA recognition by human mitochondrial alanyl-tRNA synthetase.

Alanyl-tRNA synthetases (AlaRSs) from three domains of life predominantly rely on a single wobble base pair, G3-U70, of tRNAAla as a major determinant. However, this base pair is divergent in human mitochondrial tRNAAla, but instead with a translocated G5-U68. How human mitochondrial AlaRS (hmtAlaRS) recognizes tRNAAla, in particular, in the acceptor stem region, remains unknown. In the present study, we found that hmtAlaRS is a monomer and recognizes mitochondrial tRNAAla in a G3-U70-independent manner, requiring several elements in the acceptor stem. In addition, we found that hmtAlaRS misactivates noncognate Gly and catalyzes strong transfer RNA (tRNA)-independent pre-transfer editing for Gly. A completely conserved residue outside of the editing active site, Arg663, likely functions as a tRNA translocation determinant to facilitate tRNA entry into the editing domain during editing. Finally, we investigated the effects of the severe infantile-onset cardiomyopathy-associated R592W mutation of hmtAlaRS on the canonical enzymatic activities of hmtAlaRS. Overall, our results provide fundamental information about tRNA recognition and deepen our understanding of translational quality control mechanisms by hmtAlaRS.

Pharmacokinetic analysis for the differentiation of pituitary microadenoma subtypes through dynamic contrast-enhanced magnetic resonance imaging.

The value of pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in distinguishing pituitary microadenoma subtypes was investigated in the present study. Pathology and follow-up outcomes were applied as the gold standard for differentiating between 76 patients with pituitary microadenomas (38 prolactin-producing tumors, 17 adrenocorticotropic hormone adenomas and 21 growth hormone-producing tumors) and 20 patients with normal pituitary glands. DCE-MRI was conducted to obtain the following quantitative permeability parameters: Volume transfer constant (Ktrans), rate constant (Kep) and extracellular extravascular volume fraction (Ve). Among the 76 cases included, 61 were visually diagnosed using conventional MRI. The Ktrans, Kep and Ve of the microadenoma cases were 0.472±0.292/min, 0.765±0.359/min and 0.792±0.345, respectively. The Ktrans, Kep and Ve of the normal control group were 0.902±0.238/min, 1.208±0.599/min and 0.928±0.378, respectively. The Ktrans and Kep of patients with microadenomas were significantly lower compared with those of the normal controls (P<0.05). However, the Ve of the two groups did not significantly differ. Subtype differentiation analysis revealed that patients with growth hormone-producing tumors exhibited the highest Ktrans value (P<0.05). Kep significantly differed between growth hormone-producing tumors and the other two subtypes (P<0.05), but did not significantly differ among three subtypes. Receiver-operator characteristic analysis indicated that the area under the curve values of Ktrans and Kep were 0.884 and 0.728, respectively. Sensitivity and specificity were 95.0 and 82.6%, respectively, when Ktrans was set to 0.614/min as the cut-off value, and when the Kep cut-off value was set to 0.985/min, sensitivity and specificity were 60.0 and 81.3%, respectively. In conclusion, Ktrans and Kep derived from DCE-MRI could be applied to detect and identify microadenoma subtypes. Ktrans better reflects the blood perfusion alterations exhibited by patients with different microadenoma subtypes.

Experimental Demonstration of Observability and Operability of Robustness of Coherence.

Quantum coherence is an invaluable physical resource for various quantum technologies. As a bona fide measure in quantifying coherence, the robustness of coherence (ROC) is not only mathematically rigorous, but also physically meaningful. We experimentally demonstrate the witness-observable and operational feature of the ROC in a multiqubit nuclear magnetic resonance system. We realize witness measurements by detecting the populations of quantum systems in one trial. The approach may also apply to physical systems compatible with ensemble or nondemolition measurements. Moreover, we experimentally show that the ROC quantifies the advantage enabled by a quantum state in a phase discrimination task.

A natural non-Watson-Crick base pair in human mitochondrial tRNAThr causes structural and functional susceptibility to local mutations.

Six pathogenic mutations have been reported in human mitochondrial tRNAThr (hmtRNAThr); however, the pathogenic molecular mechanism remains unclear. Previously, we established an activity assay system for human mitochondrial threonyl-tRNA synthetase (hmThrRS). In the present study, we surveyed the structural and enzymatic effects of pathogenic mutations in hmtRNAThr and then focused on m.15915 G > A (G30A) and m.15923A > G (A38G). The harmful evolutionary gain of non-Watson-Crick base pair A29/C41 caused hmtRNAThr to be highly susceptible to mutations disrupting the G30-C40 base pair in various ways; for example, structural integrity maintenance, modification and aminoacylation of tRNAThr, and editing mischarged tRNAThr. A similar phenomenon was observed for hmtRNATrp with an A29/C41 non-Watson-Crick base pair, but not in bovine mtRNAThr with a natural G29-C41 base pair. The A38G mutation caused a severe reduction in Thr-acceptance and editing of hmThrRS. Importantly, A38 is a nucleotide determinant for the t6A modification at A37, which is essential for the coding properties of hmtRNAThr. In summary, our results revealed the crucial role of the G30-C40 base pair in maintaining the proper structure and function of hmtRNAThr because of A29/C41 non-Watson-Crick base pair and explained the molecular outcome of pathogenic G30A and A38G mutations.

Experimental demonstration of nonlinear quantum metrology with optimal quantum state.

Nonlinear quantum metrology may exhibit better precision scalings. For example, the uncertainty of an estimated phase may scale as Δϕ∝1/N2 under quadratic phase accumulation, which is 1/N times smaller than the linear counterpart, where N is probe number. Here, we experimentally demonstrate the nonlinear quantum metrology by using a spin-I (I>1/2) nuclear magnetic resonance (NMR) ensemble that can be mapped into a system of N=2I spin-1/2 particles and the quadratic interaction can be utilized for the quadratic phase accumulation. Our experimental results show that the phase uncertainty can scale as Δϕ∝1/(N2-1) by optimizing the input states, when N is an odd number. In addition, the interferometric measurement with quadratic interaction provides a new way for estimating the quadrupolar coupling strength in an NMR system. Our system may be further extended to exotic nonlinear quantum metrology with higher order many-body interactions.