Triptolide induced spermatogenesis dysfunction via ferroptosis activation by promoting K63-linked GPX4 polyubiquitination in spermatocytes.

Triptolide (TP) is a major bioactive compound derived from Tripterygium wilfordii Hook. F. (TwHF) known for its medicinal properties, but it also exhibits potential toxic effects. It has been demonstrated to induce severe male reproductive toxicity, yet the precise mechanism behind this remains unclear, which limits its broad clinical application. This study aimed to investigate the mechanisms underlying testicular damage and spermatogenesis dysfunction induced by TP in mice, using both mouse models and the spermatocyte-derived cell line GC-2spd. In the present study, it was found that TP displayed significant testicular microstructure damaged and spermatogenesis defects including lower concentration and abnormal morphology by promoting ROS formation, MDA production and restraining GSH level, glutathione peroxidase 4 (GPX4) expression in vivo. Furthermore, Ferrostatin-1 (FER-1), a ferroptosis inhibitor, was found to significantly reduce the accumulation of lipid peroxidation, alleviate testicular microstructural damage, and enhance spermatogenic function in mice. Besides, notably decreased cell viability, collapsed mitochondrial membrane potential, and elevated DNA damage were observed in vitro. The above-mentioned phenomenon could be reversed by pre-treatment of FER-1, indicating that ferroptosis participated in the TP-mediated spermatogenesis dysfunction. Mechanistically, TP could enhance GPX4 ubiquitin degradation via triggering K63-linked polyubiquitination of GPX4, thereby stimulating ferroptosis in spermatocytes. Functionally, GPX4 deletion intensified ferroptosis and exacerbated DNA damage in GC-2 cells, while GPX4 overexpression mitigated ferroptosis induced by TP. Overall, these findings for the first time indicated a vital role of ferroptosis in TP induced-testicular injury and spermatogenic dysfunction through promoting GPX4 K63-linked polyubiquitination, which hopefully offers a potential therapeutic avenue for TP-related male reproductive damage. In addition, this study also provides a theoretical foundation for the improved clinical application of TP or TwHF in the future.

In Situ-Initiated Poly-1,3-dioxolane Gel Electrolyte for High-Voltage Lithium Metal Batteries.

To realize high-energy-density Li metal batteries at low temperatures, a new electrolyte is needed to solve the high-voltage compatibility and fast lithium-ion de-solvation process. A gel polymer electrolyte with a small-molecular-weight polymer is widely investigated by combining the merits of a solid polymer electrolyte (SPE) and liquid electrolyte (LE). Herein, we present a new gel polymer electrolyte (P-DOL) by the lithium difluoro(oxalate)borate (LiDFOB)-initiated polymerization process using 1,3-dioxolane (DOL) as a monomer solvent. The P-DOL presents excellent ionic conductivity (1.12 × 10-4 S cm-1) at -20 °C, with an oxidation potential of 4.8 V. The Li‖LiCoO2 cell stably cycled at 4.3 V under room temperature, with a discharge capacity of 130 mAh g-1 at 0.5 C and a capacity retention rate of 86.4% after 50 cycles. Moreover, a high-Ni-content LiNi0.8Co0.1Mn0.1O2 (NCM811) cell can steadily run for 120 cycles at -20 °C, with a capacity retention of 88.4%. The underlying mechanism of high-voltage compatibility originates from the dense and robust B- and F-rich cathode interface layer (CEI) formed at the cathode interface. Our report will shed light on the real application of Li metal batteries under all-climate conditions in the future.

A neural circuit for regulating a behavioral switch in response to prolonged uncontrollability in mice.

Persistence in the face of failure helps to overcome challenges. But the ability to adjust behavior or even give up when the task is uncontrollable has advantages. How the mammalian brain switches behavior when facing uncontrollability remains an open question. We generated two mouse models of behavioral transition from action to no-action during exposure to a prolonged experience with an uncontrollable outcome. The transition was not caused by pain desensitization or muscle fatigue and was not a depression-/learned-helplessness-like behavior. Noradrenergic neurons projecting to GABAergic neurons within the orbitofrontal cortex (OFC) are key regulators of this behavior. Fiber photometry, microdialysis, mini-two-photon microscopy, and tetrode/optrode in vivo recording in freely behaving mice revealed that the reduction of norepinephrine and downregulation of alpha 1 receptor in the OFC reduced the number and activity of GABAergic neurons necessary for driving action behavior resulting in behavioral transition. These findings define a circuit governing behavioral switch in response to prolonged uncontrollability.

Cortical feedback modulates distinct critical period development in mouse visual thalamus.

In primary visual cortex (V1), critical period for ocular dominance (OD) plasticity is a well-defined developmental stage to shape neuronal circuits based on visual experience. Recent studies showed that V1-like OD plasticity existed in mouse dorsal lateral geniculate nucleus (dLGN). It is still unclear what the exact time window is and how neural circuits contribute to OD plasticity in dLGN. Using in vivo electrophysiology, we defined a critical period for OD plasticity in dLGN from eye opening to puberty. There also existed an innate process of OD formation from contralateral to equal bias in dLGN binocular neurons. Instant V1 inactivation with muscimol had no effect on OD bias or plasticity. Short-term V1 inactivation with N-methyl-d-aspartate reversed the formation of equal OD bias, while long-term V1 inactivation retained dLGN development to an immature stage.

T- and pH-dependent OH radical reaction kinetics with glycine, alanine, serine, and threonine in the aqueous phase.

Glycine, alanine, serine, and threonine are essential amino acids originating from biological activities. These substances can be emitted into the atmosphere directly. In the present study, the aqueous phase reaction kinetics of hydroxyl radicals (˙OH) with the four amino acids is investigated using the competition kinetics method under controlled temperature and pH conditions. The following T-dependent Arrhenius expressions are derived for the ˙OH reactions with glycine, k(T, H2A+) = (9.1 ± 0.3) × 109 × exp[(-2360 ± 230 K)/T], k(T, HA±) = (1.3 ± 0.1) × 1010 × exp[(-2040 ± 240 K)/T]; alanine, k(T, H2A+) = (1.4 ± 0.1) × 109 × exp[(-1120 ± 320 K)/T], k(T, HA±) = (5.5 ± 0.2) × 109 × exp[(-1300 ± 200 K)/T]; serine, k(T, H2A+) = (1.1 ± 0.1) × 109 × exp[(-470 ± 150 K)/T], k(T, HA±) = (3.9 ± 0.1) × 109 × exp[(-720 ± 130 K)/T]; and threonine, k(T, H2A+) = (5.0 ± 0.1) × 1010 × exp[(-1500 ± 100 K)/T], k(T, HA±) = (3.3 ± 0.1) × 1010 × exp[(-1320 ± 90 K)/T] (in units of L mol-1 s-1). The energy barriers of the ˙OH-induced H atom abstractions were simulated by the density functional theory (DFT) calculation performed with GAUSSIAN using the method of M06-2X and the basis set of 6-311++G(3df,2p). According to the calculation results, the -COOH and -NH3+ groups with strong negative inductive effects increase the energy barriers and thus decrease the ˙OH reaction rate constants. In contrast, the presence of a -OH or -CH3 group with weak negative or positive inductive effects can reduce energy barriers and hence increase the ˙OH reaction rate constants. To improve the previous structure-activity relationship, the contribution factors of -NH3+ at Cα-atom and Cß-atom are determined as 0.07 and 0.15, respectively. Aqueous phase ˙OH oxidation acts as an important sink of the amino acids in the atmosphere, and can be accurately described by the obtained Arrhenius expressions under atmospheric conditions.

A knowledge graph-based method for epidemic contact tracing in public transportation.

Contact tracing is an effective measure by which to prevent further infections in public transportation systems. Considering the large number of people infected during the COVID-19 pandemic, digital contact tracing is expected to be quicker and more effective than traditional manual contact tracing, which is slow and labor-intensive. In this study, we introduce a knowledge graph-based framework for fusing multi-source data from public transportation systems to construct contact networks, design algorithms to model epidemic spread, and verify the validity of an effective digital contact tracing method. In particular, we take advantage of the trip chaining model to integrate multi-source public transportation data to construct a knowledge graph. A contact network is then extracted from the constructed knowledge graph, and a breadth-first search algorithm is developed to efficiently trace infected passengers in the contact network. The proposed framework and algorithms are validated by a case study using smart card transaction data from transit systems in Xiamen, China. We show that the knowledge graph provides an efficient framework for contact tracing with the reconstructed contact network, and the average positive tracing rate is over 96%.