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Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells. Pharmacological induction of excessively asymmetric mitofission-associated cell death (MFAD) by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy. By screening a series of pan-inhibitors, we identified pracinostat, a pan-histone deacetylase (HDAC) inhibitor, as a novel MFAD inducer, that exhibited a significant anticancer effect on colorectal cancer (CRC) in vivo and in vitro. Pracinostat increased the expression of cyclin-dependent kinase 5 (CDK5) and induced its acetylation at residue lysine 33, accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynamin-related protein 1 (Drp1)-mediated mitochondrial peripheral fission. CRC cells with high level of CDK5 (CDK5-high) displayed midzone mitochondrial division that was associated with oncogenic phenotype, but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells. Mechanistically, pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor (MFF) to mitochondrial fission 1 protein (FIS1). Thus, our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells, which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.

The insect cuticle consists of chitin and cuticular proteins (CPs), which stabilize the body shape and provide an effective physical barrier against the external environment. They are also potential target sites for developing environmentally friendly insect management through the utilization of physiology-based methods. The codling moth, Cydia pomonella, is a pest afflicting fruit orchards worldwide. This study used a comparative genomic approach, whole-genome resequencing, and transcriptome data to understand the role that CPs played in the environmental adaptation of the codling moth. A total of 182 putative CPs were identified in the codling moth genome, which were classified into 12 CP families. 119 CPR genes, including 54 RR-1, 60 RR-2, and 5 RR-3 genes were identified and accounted for 65.4% of the total CPs. Eight and seven gene clusters are formed in RR1 and RR2 subfamily and the ancestor-descendant relationship was explained. Five CPAP genes were highly expressed during the egg stage and exposed to high temperature, which indicated their potential role in aiding codling moth eggs in acclimating to varying external heat conditions. Moreover, six CPs belonging to the CPR and CPLCP families were identified in association with insecticide resistance by population resequencing. Their expression levels increased after exposure to insecticides, suggesting they might be involved in codling moth resistance to the insecticides azinphos-methyl or deltamethrin. Our results provide insight into the evolution of codling moth CPs and their association with high temperature adaptation and insecticide resistance, and provide an additional information required for further analysis of CPs in environmental adaptation.

Abstract To investigate the sex, age, role and geographic differences in traumatic spinal fractures (TSFs) caused by motor vehicle collisions (MVCs) in adults (≥ 18 years old). This was a multicentre retrospective observational study. In total, 798 patients with TSFs caused by MVCs admitted to our hospitals from January 2013 to December 2019 were enrolled. The patterns were summarized with respect to different sexes (male and female), age group (18–60 and ≥ 60), role (driver, passenger and pedestrian) and geographic location (Chongqing and Shenyang). Significant differences in distribution related to district (p = 0.018), role (p

Abstract Lung adenocarcinoma (LAC) is one of the most common pulmonary adenocarcinomas with a high peak of mortality, and metastasis is the main culprit of LAC deaths. microRNAs play important role in cancer metastasis, and thus are regarded as potential diagnostic and prognostic markers for human cancers. However, many miRNAs exhibit dual roles in diverse cellular contexts. Here, we revealed that hsa‐miR‐335, a previously reported tumor suppressor, exhibited an oncogenic role in LAC. Overexpression of miR‐335 enhanced the abilities of A549 and H1299 cells to invade and migrate by regulating epithelial‐mesenchymal transition, while inhibition of miR‐335 exhibited an opposite effect in vitro and in vivo. Mechanically, miR‐335 inhibited the expression of Copine‐1 (CPNE1), an NF‐κB suppressor, through interacting with its mRNA 3′UTR, while mutating the binding sites abolished this inhibitory effect. This finding not only highlights the suppressive effect of CPNE1 on cell motility, but also provides new insight into miR‐335 in promoting LAC metastasis.

Sirtuin-1 (SIRT1) is a critical nuclear deacetylase that participates in a wide range of biological processes. We hereby employed quantitative acetyl-proteomics to globally reveal the landscape of SIRT1-dependent acetylation in colorectal cancer (CRC) cells stimulated by specific SIRT1 inhibitor Inauhzin (INZ). We strikingly observed that SIRT1 inhibition enhances protein acetylation levels, with the multisite-acetylated proteins (acetyl sites >4/protein) mainly enriched in mitochondria. INZ treatment increases mitochondrial fission and depolarization in CRC cells. The acetylation of mitochondrial proteins promoted by SIRT1 inhibition prevents the recruitment of ubiquitin and LC3 for mitophagic degradation. We then found that, SIRT1 inhibition increases the acetylation of mitochondrial calcium uniporter (MCU) at residue K332, resulting in mitochondrial Ca2+ overload and depolarization, and ultimately CRC apoptosis. Arginine substitution of the K332 (K332R) dramatically decreases the mitochondrial Ca2+ influx, mitochondrial membrane potential loss and ROS burst induced by INZ. This finding uncovers a non-canonical role of SIRT1 in regulating mitochondrial function and implicates a possible way for anticancer intervention through SIRT1 inhibition.

Rab5 is a small GTPase that plays a crucial role in oncogenic signal transduction, which was considered as an attractive target for cancer therapy. Rapid GDP/GTP exchange in the packet of Rab5 sustains its high activity for promoting cancer progression. However, Rab5 currently remains undruggable due to the lack of specific inhibitor. Herein, we reported the discovery of a novel Rab5 inhibitor, neoandrographolide (NAP), by using high-throughput virtual screening with a natural product library containing 7459 compounds, which can occupy the surface groove of Rab5, competing with GDP/GTP for the binding. Ser34 is the most important residue in the groove of Rab5, as it forms most hydrogen-bond interactions with GDP/GTP or NAP, and in silico mutation of Ser34 decreased the stabilization of Rab5. Moreover, fluorescence titration experiment and isothermal titration calorimetry (ITC) assay revealed a direct binding between NAP and Rab5. Biochemical and cell-based assays showed that NAP treatment not only diminished the activity of Rab5, but also suppressed cell growth of cancer cell. This finding firstly identifies NAP as a novel inhibitor of Rab5, which directly binds with Rab5 by occupying the GDP/GTP binding groove to suppress its functions, highlighting a great potential of NAP to be developed as a chemotherapeutic agent in cancer therapy.

As environmentally friendly materials, carbon black and bio-oil can be used as modifiers to effectively enhance the poor high-temperature and low-temperature performance of base asphalt and its mixture. Different carbon black and bio-oil contents and shear time were selected as the test influencing factors in this work. Based on the Box–Behnken design (BBD), carbon black/bio-oil composite modified asphalt was prepared to perform the softening point, penetration, multiple stress creep and recovery (MSCR), and bending beam rheometer (BBR) tests. The response surface method (RSM) was used to analyze the test results. In addition, the base asphalt mixtures and the optimal performance carbon black/bio-oil composite modified asphalt mixtures were formed for rutting and low-temperature splitting tests. The results show that incorporating carbon black can enhance the asphalt’s high-temperature performance by the test results of irrecoverable creep compliance (Jnr) and strain recovery rate (R). By contrast, the stiffness modulus (S) and creep rate (M) test results show that bio-oil can enhance the asphalt’s low-temperature performance. The quadratic function models between the performance indicators of carbon black/bio-oil composite modified asphalt and the test influencing factors were established based on the RSM. The optimal performance modified asphalt mixture’s carbon black and bio-oil content was 15.05% and 9.631%, and the shear time was 62.667 min. It was revealed that the high-temperature stability and low-temperature crack resistance of the carbon black/bio-oil composite modified asphalt mixture were better than that of the base asphalt mixture because of its higher dynamic stability (DS) and toughness. Therefore, carbon black/bio-oil composite modified asphalt mixture can be used as a new type of choice for road construction materials, which is in line with green development.

The judicious use of steroid preparations under polythene film has revolutionized the treatment of chronic psoriasis and other intractable genodermatoses such as atopic eczema. However, occlusive therapy can be tedious and many patients who have established satisfactory control with occlusion become neglectful in its use and suffer disappointing recurrences. There is no suitable alternative treatment for those patients, who must persist with occlusion in order to maintain maximal control of their dermatoses, other than methotrexate and/or oral steroids. It would indeed be ideal if a relatively inexpensive topical steroid could be presented In a base so penetrating that it would obviate the need for occlusion in the management of persistent recurring dermatoses. [ABSTRACT FROM AUTHOR]

Cryopreservation was attempted using a partial dehydration and freezing protocol on pomelo (Citrus grandis) seeds of ten cultivars and embryonic axes of one cultivar collected from Xishuangbanna. Although seeds of all ten cultivars could be dehydrated safely to 10 percent moisture content, further dehydration impaired seed viability with critical moisture contents ranging from 9 percent to 7 percent. Complete seedling regenerated from seeds frozen in a moisture window between 5-9 percent, and maximum seedling recovery varied between 22-86 percent. Cryopreservation of Jiajieyou cv. embryonic axes had a moisture window between 3-20 percent , much wider compared to whole seed cryopreservation, and maximum post-thaw emergence of 93 percent was achieved at 13 percent moisture content. Emergence differed only slightly from survival when whole seeds were cryopreserved, but for the embryonic axis cryopreservation at low moisture contents resulted in much lower emergence than survival. Possible causes of intraspecific variation in cryotolerance in pomelo seeds is discussed.

Introduction: Dihydrotestosterone (DHT) is a steroid hormone derived from testosterone, by the action of two distinct isoenzymes (type 1 and 2) of 5-alpha-reductase. Dutasteride is a specific selective inhibitor of the two isoenzymes, while finasteride is a selective inhibitor of type 2 -alpha-reductase. The working hypothesis is that the double 5-alpha-reductase inhibition induced by dutasteride therapy for 6 weeks should induce a supplementary reduction of plasma DHT levels compared to a parallel patient group continuing finasteride therapy over the same period., Materials and Methods: In this prospective, two-centre, double-blind study, 21 patients previously treated by finasteride 5 mg for benign prostatic hyperplasia (BPH) for at least 6 months were randomized to receive either dutasteride 0.5 mg, or finasteride 5 mg daily for 6 weeks., Results: The mean relative variation of plasma DHT was 67.3% +/- 16.16% in the dutasteride group and 30.3% +/- 59.8% in the finasteride group. The reduction of DHT was numerically greater and more constant in the dutasteride group than in the finasteride group at 6 weeks; such a tendency was already observed after two weeks of treatment with dutasteride. Nevertheless, these differences were not statistically significant. Both medications were well tolerated and the only treatment-related adverse event (epigastric pain) was reported in the finasteride group., Conclusions: The working hypothesis was therefore not statistically confirmed. It is difficult to conclude whether this reflects poor patient compliance with long-term finasteride for BPH or variability of response in patients with good compliance with treatment.