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Pyruvate kinase isoform M2 (PKM2) plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions. Here, we report that SAICAR (succinylaminoimidazolecarboxamide ribose-5'-phosphate, an intermediate of the de novo purine nucleotide synthesis pathway) specifically stimulates PKM2. Upon glucose starvation, cellular SAICAR concentration increased in an oscillatory manner and stimulated PKM2 activity in cancer cells. Changes in SAICAR amounts in cancer cells altered cellular energy level, glucose uptake, and lactate production. The SAICAR-PKM2 interaction also promoted cancer cell survival in glucose-limited conditions. SAICAR accumulation was not observed in normal adult epithelial cells or lung fibroblasts, regardless of glucose conditions. This allosteric regulation may explain how cancer cells coordinate different metabolic pathways to optimize their growth in the nutrient-limited conditions commonly observed in the tumor microenvironment.

Interstitial lung disease (ILD), particularly idiopathic pulmonary fibrosis (IPF), has a poor prognosis. Corticosteroids are widely used in the treatment of acute exacerbation of ILD (AE-ILD). This study aimed to clarify the causes of AE-ILD, determine the efficacy of corticosteroids for treating AE-ILD, and detect differences in the mortality rate among subgroups of ILD. This was an observational retrospective single-center study. Patients with ILD who presented to the emergency department with acute respiratory symptoms from January 1, 2016, to December 31, 2018, were included. Patients with AE-ILD were classified into two groups depending on the prednisolone dose: low dose (0 to 1.0 mg/kg) or high dose (> 1.0 mg/kg). Mortality rates between patients with and without IPF were compared. This study included 182 patients with AE-ILD, including IPF (n = 117) and non-IPF (n = 65). Multivariate Cox regression analysis showed that corticosteroid dose (HR: 0.221, CI: 0.102–0.408, P  < 0.001), initial P/F ratio (HR:0.995, CI:0.992–0.999, P  = 0.006), and mechanical ventilation within 3 days of hospitalization (HR:4.205, CI:2.059–8.589, P  < 0.001) were independent risk factors for mortality in patients with AE-ILD. This study showed that outcomes improve with higher doses of corticosteroids (> 1 mg/kg prednisolone) in patients with AE-non-IPF-ILD. However, this was not the case in patients with AE-IPF.

DNA polymerase ζ (Pol ζ) is a eukaryotic B-family DNA polymerase that specializes in translesion synthesis and is essential for normal embryogenesis. At a minimum, Pol ζ consists of a catalytic subunit Rev3 and an accessory subunit Rev7. Mammalian Rev3 contains >3,000 residues and is twice as large as the yeast homolog. To date, no vertebrate Pol ζ has been purified for biochemical characterization. Here we report purification of a series of human Rev3 deletion constructs expressed in HEK293 cells and identification of a minimally catalytically active human Pol ζ variant. With a tagged form of an active Pol ζ variant, we isolated two additional accessory subunits of human Pol ζ, PolD2 and PolD3. The purified four-subunit Pol ζ4 (Rev3–Rev7–PolD2–PolD3) is much more efficient and more processive at bypassing a 1,2-intrastrand d(GpG)-cisplatin cross-link than the two-subunit Pol ζ2 (Rev3–Rev7). We show that complete bypass of cisplatin lesions requires Pol η to insert dCTP opposite the 3′ guanine and Pol ζ4 to extend the primers.

The role of the gut microbiome in the development of renal stone diseases has not been well characterized . This study focused on the taxonomic and functional profiles of gut microbiomes according to the prevalence and incidence of nephrolithiasis. Stool samples from 915 Korean adults were collected at baseline. Participants were followed for a median of 4.0 years. We evaluated the biodiversity of the gut microbiota and taxonomic profiles associated with nephrolithiasis status, using 16S rRNA gene sequencing. Nephrolithiasis status was categorized into three groups: control (no-stone at both baseline and follow-up visits), incidental nephrolithiasis, and prevalent nephrolithiasis. Compared to the control and incidental nephrolithiasis, the prevalent nephrolithiasis showed a reduced evenness in alpha diversity. Nephrolithiasis was associated with a reduced abundance of some key taxa involved in short-chain fatty acid production. Moreover, the abundance of Bifidobacterium, which possess oxalate-degrading ability, was higher in the control. Conversely, there was no significant difference in the bacterial composition between the incidental and prevalent nephrolithiasis. In our study with repeated nephrolithiasis measurements, prevalent renal stones were associated with an altered gut microbiota composition compared to the control. Besides the known oxalate degradation pathway, other functional pathways inferred in this study require further investigation.

Senescent cells exhibit a reduced response to intrinsic and extrinsic stimuli. This diminished reaction may be explained by the disrupted transmission of nuclear signals. However, this hypothesis requires more evidence before it can be accepted as a mechanism of cellular senescence. A proteomic analysis of the cytoplasmic and nuclear fractions obtained from young and senescent cells revealed disruption of nucleocytoplasmic trafficking (NCT) as an essential feature of replicative senescence (RS) at the global level. Blocking NCT either chemically or genetically induced the acquisition of an RS-like senescence phenotype, named nuclear barrier-induced senescence (NBIS). A transcriptome analysis revealed that, among various types of cellular senescence, NBIS exhibited a gene expression pattern most similar to that of RS. Core proteomic and transcriptomic patterns common to both RS and NBIS included upregulation of the endocytosis-lysosome network and downregulation of NCT in senescent cells, patterns also observed in an aging yeast model. These results imply coordinated aging-dependent reduction in the transmission of extrinsic signals to the nucleus and in the nucleus-to-cytoplasm supply of proteins/RNAs. We further showed that the aging-associated decrease in Sp1 transcription factor expression was critical for the downregulation of NCT. Our results suggest that NBIS is a modality of cellular senescence that may represent the nature of physiological aging in eukaryotes. Aging: Communication defects between nucleus and cytoplasm Disruption of signals passing into or out of nucleus may be involved in aging. As cells age, they become senescent, i.e., stop growing and dividing. Cellular senescence is charateristic of reduced responsiveness to various stresses. Recent studies have noted that communication between nucleus and cytoplasm is dysfunctional in senescent cells. But it has not been determined whether the defects in this communication brings to cellular aging. Sang Chul Park and co-workers at DGIST, KRIBB, CNU and SNU in South Korea investigated nuclear–cytoplasmic trafficking (NCT) in senescent cells and found that impairment of NCT caused cells to become senescent. As cells aged, transmission of signals into or out of nucleus was reduced. Studying cells in which NCT is deliberately blocked may illuminate how cells age.

Lightning strikes can cause significant damage to critical infrastructure and pose a serious threat to public safety. To ensure the safety of facilities and investigate the causes of lightning accidents, we propose a cost-effective design method for a lightning current measuring instrument that uses a Rogowski coil and dual signal conditioning circuits to detect a wide range of lightning currents, ranging from hundreds of A to hundreds of kA. To implement the proposed lightning current measuring instrument, we design signal conditioning circuits and software capable of detecting and analyzing lightning currents from ±500 A to ±100 kA. By employing dual signal conditioning circuits, it offers the advantage of detecting a wide range of lightning currents compared to existing lightning current measuring instruments. The proposed instrument has the following features: First, the peak current, polarity, T1 (front time), T2 (time to half value), and Q (amount of energy of the lightning current) can be analyzed and measured with a fast sampling time of 380 ns. Second, it can distinguish whether a lightning current is induced or direct. Third, a built-in SD card is provided to save the detected lightning data. Finally, it provides Ethernet communication capability for remote monitoring. The performance of the proposed instrument is evaluated and validated by applying induced and direct lightning using a lightning current generator.

Ultraviolet (UV) B exposure induces DNA damage and production of reactive oxygen species (ROS), which causes skin photoaging through signaling pathways of inflammation and modulation of extracellular matrix remodeling proteins, collagens, and matrix metalloproteinase (MMP). As low molecular-weight fucoidan (LMF) has potential antioxidant and anti-inflammatory properties, we examined the protective effects of LMF against UVB-induced photoaging. A UVB-irradiated mouse model was topically treated with myricetin or LMF at 2.0, 1.0 and 0.2 mg/cm2 (LMF2.0, LMF1.0 and LMF0.2, respectively) once a day for 15 weeks. Wrinkle formation, inflammation, oxidative stress, MMP expression, and apoptosis in the treated regions were compared with those in a distilled water-treated photoaging model (UVB control). LMF treatments, particularly LMF2.0 and LMF1.0, significantly inhibited the wrinkle formation, skin edema, and neutrophil recruitment into the photo-damaged lesions, compared with those in the UVB control. While LMF decreased interleukin (IL)-1β release, it increased IL-10. The LMF treatment inhibited the oxidative stresses (malondialdehyde and superoxide anion) and enhanced endogenous antioxidants (glutathione). Additionally, LMF reduced the mRNA expression of MMP-1, 9, and 13. The histopathological analyses revealed the anti-photoaging effects of LMF exerted via its antioxidant, anti-apoptotic, and MMP-9-inhibiting effects. These suggest that LMF can be used as a skin-protective remedy for photoaging.

While reactive oxygen species (ROS) is generally considered harmful, a relevant amount of ROS is necessary for a number of cellular functions, including the intracellular signal transduction. In order to deal with an excessive amount of ROS, organisms are equipped with a sufficient amount of antioxidants together with NF-E2-related factor-2 (NRF2), a transcription factor that plays a key role in the protection of organisms against environmental or intracellular stresses. While the NRF2 activity has been generally viewed as beneficial to preserve the integrity of organisms, recent studies have demonstrated that cancer cells hijack the NRF2 activity to survive under the oxidative stress and, therefore, a close check must be kept on the NRF2 activity in cancer. In the present review, we briefly highlight important progresses in understanding the molecular mechanism, structure, and function of KEAP1 and NRF2 interaction. In addition, we provide general perspectives that justify conflicting views on the NRF2 activity in cancer.

Abnormal adenylosuccinate lyase (ADSL) activity is associated with cancer and neurodevelopmental processes. However, a cell-permeable ADSL inhibitor is not yet available. Our high-throughput screen identified NF-449 as a potential lead compound. To improve cell permeability of the lead compound, fragments of NF-449 were synthesized. This fragment, 2,2’-(1,3-phenylenebis(carbonylimino))-bisbenzenesulfonate, competitively inhibits purified human ADSL with an inhibitory constant of 0.4 micromolar. Its triethylammonium salt inhibited ADSL in HeLa cells with an IC50 of 0.4 micromolar. While this compound might not be ready for in vivo applications yet, further improvement in its permeability might produce useful reagents for in vivo studies of ADSL.