A Structural Comparison of Oral SARS-CoV-2 Drug Candidate Ibuzatrelvir Complexed with the Main Protease (Mpro) of SARS-CoV-2 and MERS-CoV.

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (Mpro) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of Mpro hinders the processing of the proteins essential for viral replication in vivo. However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 Mpro at 2.0 Šresolution. In addition, we show that ibuzatrelvir also potently inhibits the Mpro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV Mpro. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with Mpro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.

Dish spliced concentrator with both uniform and focused performance through a variable focal length.

We present a dish spliced concentrator (DSC) featuring hexagonal spherical sub-mirrors of uniform size. The DSC offers advantages over traditional parabolic dish concentrators, including a compact layout, cost-effectiveness, higher concentration ratio, and improved light uniformity. Its versatility allows for both uniform and focused light concentration by adjusting parameters like the focal length of the DSC, making it suitable for concentrating photovoltaic (CPV) and concentrating solar thermal (CST) applications. We design the DSC using three-dimensional (3D) vector rotation theory, implementing ray tracing and transmission characteristic analysis based on three-dimensional vector reflection theory. We establish a simulation model to evaluate the impact of geometric parameters on the DSC's optical performance.

Design of a compact off-axis two-mirror freeform optical antenna for shaping and transmitting an elliptical beam emitted by laser diode.

Elliptical Gaussian beams generated by laser diodes (LDs) often exhibit asymmetrical divergence angle distribution, which limits their practical applications. In this study, we propose what we believe is a novel approach to shape and collimate the elliptical output beam from a LD. The design process involves the construction of two freeform reflective surfaces on a reference circle using a three-dimensional point-by-point iterative method, based on the law of conservation of energy, the vector reflection theory, and Fermat's principle. The output beam's maximum divergence angle is effectively compressed to 3.1579 mrad. The design is compact with a folded optical path and antenna size of 368.8c m 3. This paper presents a comprehensive design and optimization process, along with an in-depth analysis of the system's performance, thereby offering novel insights for emerging optical design practitioners.

Global caustic and phase chirality reversal of the focused vortex beam.

We predict the reversal of the phase chirality before and after the focal plane during propagation based on ray tracing. The interference patterns of a focused vortex beam (FVB) and a plane beam during propagation verify the fact of phase chirality reversal through diffraction theoretical simulations and experiments. Also, we deduce an analytical expression for the caustic based on the ray equation, which effectively represents the change of the hollow light field during propagation. Simulation and experimental results demonstrate the effectiveness of the caustic in describing the variation of the global hollow dark spot radius. Furthermore, based on the caustic results at the focal plane, we customize FVBs with the same dark spot radii but different topological charges. Our research results reveal the characteristics of the light field and phase distribution of the FVB during propagation, which will expand our understanding of the properties of the FVB and provide a reference value for applications such as chiral particle manipulation and topological charge recognition.

Exosomes Derived from Hypoxic Glioma Cells Reduce the Sensitivity of Glioma Cells to Temozolomide Through Carrying miR-106a-5p.

Background: Hypoxia is a frequent feature of solid tumors which significantly affects the efficacy of treatments such as chemotherapy. In addition, exosomes from hypoxic cancer cells could contribute to the chemoresistance of tumor cells through carrying miRNAs. It has been shown that miR-106-5p level was upregulated in glioma. However, whether exosomes derived from hypoxic glioma cells could affect temozolomide (TMZ) resistance in glioma through carrying miR-106a-5p remains unexplored. Methods: Exosomes were isolated from glioma cells under normoxia or hypoxia condition. EdU staining and flow cytometry assays were used to assess the cell proliferation and cell apoptosis. The relation between miR-106a-5p and PTEN was investigated by dual luciferase assay. Results: MiR-106a-5p was enriched in exosomes derived from hypoxic glioma cells compared to exosomes from cells under normoxia condition. Additionally, hypoxic glioma cells were able to transfer exosomes to glioma cells, resulting in a significant increase of miR-106a-5p level in cells. TMZ remarkably suppressed glioma cell proliferation and triggered cell apoptosis. However, hypoxic glioma cell-derived exosomes markedly promoted the proliferation and suppressed the apoptosis in TMZ-treated glioma cells, and miR-106a-5p inhibitor was able to abolish these phenomena. Meanwhile, PTEN was verified to be a direct target of miR-106a-5p. Furthermore, TMZ elevated PTEN and Bax level and reduced p-Akt level in glioma cells, whereas these changes were reversed by hypoxia glioma cell-derived exosomes. Furthermore, hypoxia glioma cell-derived exosomes reduced the sensitivity of glioma cells to TMZ in vivo via downregulating PTEN. Conclusion: Collectively, exosomal miR-106a-5p derived from hypoxia glioma cells could reduce the sensitivity of glioma cells to TMZ through downregulating PTEN. Thus, our study might provide new strategies for improving the clinical efficacy of TMZ on glioma.

High Strength and Low Coercivity of Cobalt with Three-Dimensional Nanoscale Stacking Faults.

Lower coercivity (HC) and magnetic anisotropy (K1) coupled with high mechanical strength are essential properties for Co-based soft magnetic thin films; however, the strength-coercivity trade-off limits their development. Co with face centered cubic structure (fcc) exhibits lower HC and K1 than its grand hexagonal close packed structure (hcp); however, metastable fcc-phase Co is hard to stabilize. Here, by using Cu (100) seed layer, we synthesized micron-thick fcc Co films with self-formed three-dimensional nanoscale stacking faults (3D-nSFs) that could achieve high strengths without sacrificing soft magnetic properties. The 3D-nSFs, induced by the Co/Cu interface, could not only stabilize the metastable fcc Co to yield lower HC but also impede dislocation motion to strengthen Co films. More importantly, we successfully tailored the density of 3D-nSFs and confirmed a large variation in magnetic coercivity (by 100%) and indentation hardness (by 25%). This work provides a new strategy for integrated performance optimization by interface design and strain engineering.

Combined EGFR and VEGFR versus single EGFR signaling pathways inhibition therapy for NSCLC: a systematic review and meta-analysis.

BACKGROUND: Lung cancer is a heterogeneous disease with multiple signaling pathways influencing tumor cell survival and proliferation, and it is likely that blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. Whether combined inhibition therapy has greater anti-tumor activity than single inhibition therapy is a matter of debate. Hence, a meta-analysis comparing therapy inhibiting both VEGFR and EGFR signaling pathways with that inhibiting EGFR signaling pathway alone was performed. METHODOLOGY AND PRINCIPAL FINDINGS: We searched PubMed, EMBASE database and the proceedings of major conferences for relevant clinical trials. Outcomes analyzed were objective tumor response rate (ORR), progression-free survival (PFS), overall survival (OS) and toxicity. Besides, subgroup analyses were performed to investigate whether the combined inhibition therapy is best performed using combination of selective agents or a single agent with multiple targets. Six trials recruiting 3,302 patients were included in the analysis. Combined inhibition therapy was associated with a 3% improvement in OS as compared with single-targeted therapy, but this difference was not statistically significant (HR, 0.97; 95% CI, 0.89-1.05; P=0.472). Patients receiving combined inhibition therapy had significant longer PFS than the group with single-targeted therapy (HR, 0.80; 95% CI, 0.67-0.95; P=0.011). There was no difference in the ORR between the groups (OR, 1.44; 95% CI, 0.95-2.18; P=0.085). Subgroup analysis revealed that combined inhibition therapy using combination regimens was associated with statistically significant improvement in both ORR and PFS. Toxicity was greater in combined inhibition therapy. CONCLUSIONS: There is no evidence to support the use of combined inhibition therapy in unselected patients with advanced NSCLC. However, given the significant advantage in ORR and PFS, combined inhibition therapy using combination regimens may be considered for further evaluation in subsets of patients who may benefit from this treatment.

Efficacy and safety of vandetanib, a dual VEGFR and EGFR inhibitor, in advanced non-small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Vandetanib, an oral inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling, has attracted wide interest in treatment of advanced non-small-cell lung cancer (NSCLC). We aimed to assess its efficacy and safety via a systematic review and meta-analysis. METHODS: Trials comparing vandetanib-based therapy and non-vandetanib therapy for advanced NSCLC were identified. Endpoints evaluated were progression-free survival (PFS), overall survival (OS), objective tumor response rate (ORR), and toxicity. RESULTS: Seven trials including 4,492 patients were included in the analysis. As compared with placebo, vandetanib yielded a clear benefit for ORR (odds ratio (OR) = 2.04; 95% CI, 1.60-2.61; P <0.001), and a clinically and statistically significant 25% improvement in PFS (hazard ratio (HR) = 0.75; 95% CI, 0.66- 0.85; P < 0.001). However, these benefits did not translate into a significant improvement in OS (HR = 0.95; 95% CI, 0.88-1.04; P = 0.291). Subgroup analyses showed that vandetanib 100mg/d was associated with greater antitumor activity than 300 mg/d when given in combination with chemotherapy. In addition, the pooled results demonstrated no statistically significant difference between vandetanib and single-targeted agents in PFS, ORR or OS. Vandetanib was associated with more frequent adverse events. CONCLUSIONS: Vandetanib, as compared with placebo, significantly increases ORR and PFS, but does not improve OS in the treatment of advanced NSCLC. As compared with single-targeted agent, vandetanib does not provide any efficacy advantage. Furthermore grade 3 or greater toxicity proved greater in the vandetanib arm.

[Report on 16 rare species of human chromosomal].

By examining the lymphocytic chromosomes of peripheral blood from patients with amenorrhea, spontaneous abortion and stillbirth history, .the 16 rare species of human chromosomal abnormal karyotypes were discovered. They were 46,XY,t(6;11)(q25;p15);46,XY,inv(3)(p25;q29);46,XY,t(7;18)(q10;p10);46,X,t(X;13)(q24;q14);46,XY,t(4;7)(q33;q22);46,XY,t(8;15)(q24;q15);46,XY,t(2;17)(q33;q25);46,XX,t(4;7)(q34;q11);46,XX,t(1;3)(p36;p23);46,XX,t(4;6)(q35;p11);46,X,inv(X)(q22;q28);46,XX,t(7;10)(p11;q26);46,XX,t(3;6)(p21;q23);46,XX,t(8;16)(p21;p13);46,XX,t(8;9)(q21;q34);46,XY,t(17;22)(q21;q11). Their clinical situation were described. Discussion on the relationship between the chromosomal aberrations and phenotype effect indicates the importance of chromosome karyotyping in patients with abnormal reproductive history.

[Analysis and application of SCA1 and SCA3/MJD gene CAG repeats in Han population in Northeastern China].

OBJECTIVE: To investigate the normal range of (CAG)n in spinocerebellar ataxia type 1 (SCA1) gene and spinocerebellar ataxia type 3 (SCA3/MJD) gene in 110 normal subjects of Han population in Northeastern China, to assess the genotypes for clinically diagnosed spinocerebellar ataxia(SCA) individuals including 25 patients from 8 families and 6 sporadic patients, and to make presymptomatic and prenatal diagnosis. METHODS: DNA fragments from the normal subjects and the patients were detected by fluorescence-PCR. Homozygosities were selected for DNA sequencing. RESULTS: The normal ranges of (CAG)n of SCA1 and SCA3/MJD were 20-39 and 14-38 repeats respectively, SCA1 was found mostly to be 26 and 27 repeats, allele frequency 34.09% and 20.91%; heterozygosity was 84.55%, SCA3/MJD was found mostly to be 14 repeats, allele frequency 39.55%, heterozygosity was 78.18%.(CAG)(68) of SCA3/MJD gene of one affected individual had been found in a family but no CAG mutative expansion in related members was observed. CONCLUSION: The normal ranges of CAG repeats vary with areas and races. SCAs genotyping is the first choice in presymptomatic and prenatal diagnosis.