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Infectious disease caused by methicillin-resistant Staphylococcus aureus (MRSA) seriously threatens public health. The design of antimicrobial peptide mimics (AMPMs) based on natural products (NPs) is a new strategy to kill MRSA and slow the development of drug resistance recently. Here, we reported the design and synthesis of novel AMPMs based on harmane skeleton. Notably, compound 9b exhibited comparable or even better anti-MRSA activity in vitro and in vivo with minimum inhibitory concentration (MIC) of 0.5–2 μg/mL than the positive drug vancomycin. The highly active compound 9b not only showed low cytotoxicity, no obvious hemolysis and good plasma stability, but also presented low tendency of developing resistance. Anti-MRSA mechanism revealed that compound 9b could destroy cell wall structure by interacting with lipoteichoic acid and peptidoglycan, cause membrane damage by depolarization, increased permeability and destructed integrity, reduce cell metabolic activity by binding to lactate dehydrogenase (LDH), interfere cellular redox homeostasis, and bind to DNA. Overall, compound 9b killed the MRSA by multi-target mechanism, which provide a promising light for combating the growing MRSA resistance. [Display omitted] • Quaternized AMPMs based on harmane are designed and synthesized. • Compound 9b possess remarkable anti-MRSA effects in vitro and in vivo. • Compound 9b slow down the development of drug resistance by multi-target mechanism. [ABSTRACT FROM AUTHOR]

The giant hyena Pachycrocuta is one of the iconic components in Eurasia Pleistocene faunas. This genus largely went extinct near the Early-Middle Pleistocene boundary in Europe, but continued to flourish till the early Middle Pleistocene in eastern Asia. However, the Middle Pleistocene Pachycrocuta in eastern Asia is only well represented in Loc. 1, 9 and 13 of Zhoukoudian, and the geographic variation is unknown. Here, a complete mandible is reported from the Middle Pleistocene loess in Luoning, Henan Province, central China. The mandible is similar to that of Pachycrocuta from Zhoukoudian in dental morphology, but is markedly larger, being the largest Pachycrocuta known (the estimated skull total length reaches 385 mm, and the estimated body mass is 150.3 kg). It also displays several unique mandibular traits, e.g., strongly curved toothrow, and elevated condyle. This suggests the presence of geographic or chronological differences between the populations of Pachycrocuta across Asia during the Middle Pleistocene. A gradually increasing depth is observed in the Pliocrocuta-Pachycrocuta lineage during its evolution, until its final extinction. [ABSTRACT FROM AUTHOR]

We analyze the anisotropic factors present in the gravitational wave signal, such as the peculiar velocity of the observer and the inhomogeneous distribution of matter in the universe. We model the gravitational wave source as a standard siren, extract the anisotropic part of its luminosity distance d L , and obtain the Hubble parameter H(z) by direct calculation instead of integration. Finally, we derive the equation of state w DE (z) for the dark energy by both model-dependent and model-independent methods, and further investigate the cosmological significance of the simulated H(z) measurements. The advantage of this approach is that it makes full use of the anisotropic part of the d L data, which directly gives the value of H(z) at certain redshifts. This approach is sensitive to the local features of H(z) and does not depend on the cosmological model. [ABSTRACT FROM AUTHOR]

In this paper, we analytically prove that the sufficient condition in Proposition 3 of Zhou and Zou (2023) never holds. In this paper, we analytically prove that the sufficient condition in proposition 3 of [Zhou B, Zou T (2023) Competing for recommendations: The strategic impact of personalized product recommendations in online marketplaces. Marketing Sci. 42(2):360–376] never holds. We provide a new sufficient condition that actually holds, and discuss its implications. History: Olivier Toubia served as the senior editor for this article. Supplemental Material: The online appendix is available at https://doi.org/10.1287/mksc.2022.0410. [ABSTRACT FROM AUTHOR]

Fine particulate matter (PM2.5)-induced male reproductive toxicity arouses global public health concerns. However, the mechanisms of toxicity remain unclear. This study aimed to further investigate toxicity pathways by exposure to PM2.5 in vitro and in vivo through the application of metabolomics and transcriptomics. In vitro , spermatocyte-derived GC-2spd cells were treated with 0, 25, 50, 100 μg/mL PM2.5 for 48 h. In vivo , the real-world exposure of PM2.5 for mouse was established. Forty-five male C57BL/6 mice were exposed to filtered air, unfiltered air, and concentrated ambient PM2.5 in Tangshan of China for 8 weeks, respectively. The results in vitro and in vivo showed that PM2.5 exposure inhibited GC-2spd cell proliferation and reduced sperm motility. Mitochondrial damage was observed after PM2.5 treatment. Increased Humanin and MOTS-c levels and decreased mitochondrial respiratory indicated that mitochondrial function was disturbed. Furthermore, nontargeted metabolomics analysis revealed that PM2.5 exposure could disturb the citrate cycle (TCA cycle) and reduce amino acids and nucleotide synthesis. Mechanically, the aryl hydrocarbon receptor (AhR) pathway was activated after exposure to PM2.5, with a significant increase in CYP1A1 expression. Further studies showed that PM2.5 exposure significantly increased both intracellular and mitochondrial reactive oxygen species (ROS) and activated NRF2 antioxidative pathway. With the RNA-sequencing technique, the differentially expressed genes induced by PM2.5 exposure were mainly enriched in the metabolism of xenobiotics by the cytochrome P450 pathway, of which Cyp1a1 was the most significantly changed gene. Our findings demonstrated that PM2.5 exposure could induce spermatocyte damage and energy metabolism disorder. The activation of the aryl hydrocarbon receptor might be involved in the mechanism of male reproductive toxicity. [ABSTRACT FROM AUTHOR]

The sabertoothed cat Megantereon is an iconic carnivore in the Pleistocene of Eurasia, yet its fossil record is extremely rare and highly fragmentary in southern China (and the whole Oriental Realm). Here we report a nearly complete and undeformed skull of Megantereon from Sabretooth Cave, Chongzuo, southernmost China, middle Early Pleistocene. The general morphology allows us to assign it to Megantereon nihowanensis, differing from the northern China population of M. nihowanensis by better developed P4 parastyle and longer c-p3 diastema. The excellent preservation allows us to exam the previous unrecognised cranial characters. Megantereon shows a clear affinity to Smilodon in many aspects, e.g. wide nasal with parallel lateral border and smoothly curved posterior border, presence of moderately developed antero-medial process of the nasal, presence of anterior accessory process of the frontal, and a distinct frontal depression behind the posterior border of the nasal. These characters are markedly different from those of Homotherium, suggesting a deep divergence of the two lineages of sabertoothed cats. The rarity of Megantereon in southern China and southeastern Asia probably suggests this genus is not well adaptive to the closed forest environment. [ABSTRACT FROM AUTHOR]

Polystyrene nanoplastics (PS-NPs) have been reported to accumulate in the testes and constitute a new threat to reproductive health. However, the exact effects of PS-NPs exposure on testicular cells and the underlying mechanisms remain largely unknown. The C57BL/6 male mice were orally administered with PS-NPs (80 nm) at different dosages (0, 10, and 40 mg/kg/day) for 60 days, and GC-1 cells were treated with PS-NPs in this study. Enlarged seminiferous tubule lumens and a loose and vacuolated layer of spermatogenic cells were observed in PS-NPs-exposed mice. Spermatogenic cells which may be one of the target cells for this reproductive damage, were decreased in the mice from PS-NPs group. PS-NPs caused spermatogenic cells to undergo senescence, manifested as elevated SA-β-galactosidase activity and activated senescence-related signaling p53-p21/Rb-p16 pathways, and induced cell cycle arrest. Mechanistically, Gene Ontology (GO) enrichment suggested the key role of reactive oxygen species (ROS) in PS-NPs-induced spermatogenic cell senescence, and this result was confirmed by measuring ROS levels. Moreover, ROS inhibition partially attenuated the senescence phenotype of spermatogenic cells and DNA damage. Using the male health atlas (MHA) database, Sirt1 was filtrated as the critical molecule in the regulation of testicular senescence. PS-NPs induced overexpression of the main ROS generator Nox2, downregulated Sirt1, increased p53 and acetylated p53 in vivo and in vitro, whereas these disturbances were partially restored by pterostilbene. In addition, pterostilbene intervention significantly alleviated the PS-NPs-induced spermatogenic cell senescence and attenuated ROS burst. Collectively, our study reveals that PS-NPs exposure can trigger spermatogenic cell senescence mediated by p53-p21/Rb-p16 signaling by regulating the Sirt1/ROS axis. Importantly, pterostilbene intervention may be a promising strategy to alleviate this damage. • Nanoplastics induced reproductive damage in male mice. • Nanoplastics triggered spermatogenic cell senescence. • Sirt1/ROS axis was involved in the nanoplastic induced spermatogenic cell senescence. • Pterostilbene intervention may be a promising strategy to alleviate nanoplastic damage. [ABSTRACT FROM AUTHOR]