Active Volcanism Revealed from a Seismicity Conduit in the Long-resting Tatun Volcano Group of Northern Taiwan.

Abundant earthquakes clustered within a particular zone often reflect an active geological feature, such as clustering seismicity along a fault zone and a huge number of volcanic-earthquakes around the erupting conduit. Herein we perform a double-difference tomographic inversion and relocate the seismicity at the long-resting Tatun volcano group (TVG) in northern Taiwan. A dramatic improvement of the earthquake location model surprisingly show that, from 2014 to 2017, two clustered seismic zones are identified in the TVG. One major group of events (>1000) persistently clustered within a ~500 m diameter vertical conduit with a ~2 km height. The clustering seismicity conduit is just located nearby Dayoukeng, one of the strongest fumaroles in the TVG, and is connected to a fracture zone characterized by low Vp/Vs in the shallow crust. The other group of events is clustered within a sphere-like zone beneath Mt. Chihsin around the depths between 0.5 km and 2 km. Both seismic zones are probably triggered by the significantly volcanic gases and fluids ascending from the deep magma reservoir. Combined with a variety of results from literature, the seismicity conduit near the strong fumarole is the evidence for an active volcano and also identifies a likely pathway for ascending magma if the TVG erupts again in the future. But possibility of developing different magma pathways at other clustered seismic zones such as beneath Mt. Chihsin may not be totally excluded.

The effect of orbital-lattice coupling on the electrical resistivity of YBaCuFeO5 investigated by X-ray absorption.

Temperature-dependent X-ray absorption near-edge structures, X-ray linear dichroism (XLD) and extended X-ray absorption fine structure (EXAFS) spectroscopic techniques were used to investigate the valence state, preferred orbital and local atomic structure that significantly affect the electrical and magnetic properties of a single crystal of YBaCuFeO5 (YBCFO). An onset of increase of resistivity at ~180 K, followed by a rapid increase at/below 125 K, is observed. An antiferromagnetic (AFM)-like transition is close to the temperature at which the resistivity starts to increase in the ab-plane and is also observed with strong anisotropy between the ab-plane and the c-axis. The XLD spectra at the Fe L3,2-edge revealed a change in Fe 3d eg holes from the preferential [Formula: see text] orbital at high temperature (300-150 K) to the [Formula: see text] orbital at/below 125 K. The analysis of the Fe K-edge EXAFS data of YBCFO further revealed an unusual increase in the Debye-Waller factor of the nearest-neighbor Fe-O bond length at/below 125 K, suggesting phonon-softening behavior, resulting in the breaking of lattice symmetry, particularly in the ab-plane of Fe-related square pyramids. These findings demonstrate a close correlation between electrical resistivity and coupling of the preferred Fe 3d orbital with lattice distortion of a single crystal of YBCFO.

Therapeutic glucocorticoids prevent bone loss but drive muscle wasting when administered in chronic polyarthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) experience extra-articular manifestations including osteoporosis and muscle wasting, which closely associate with severity of disease. Whilst therapeutic glucocorticoids (GCs) reduce inflammation in RA, their actions on muscle and bone metabolism in the context of chronic inflammation remain unclear. We utilised the TNF-tg model of chronic polyarthritis to ascertain the impact of therapeutic GCs on bone and muscle homeostasis in the context of systemic inflammation. METHODS: TNF-tg and wild-type (WT) animals received either vehicle or the GC corticosterone (100 µg/ml) in drinking water at onset of arthritis. Arthritis severity and clinical parameters were measured, serum collected for ELISA and muscle and bone biopsies collected for µCT, histology and mRNA analysis. In vivo findings were examined in primary cultures of osteoblasts, osteoclasts and myotubes. RESULTS: TNF-tg mice receiving GCs showed protection from inflammatory bone loss, characterised by a reduction in serum markers of bone resorption, osteoclast numbers and osteoclast activity. In contrast, muscle wasting was markedly increased in WT and TNF-tg animals receiving GCs, independently of inflammation. This was characterised by a reduction in muscle weight and fibre size, and an induction in anti-anabolic and catabolic signalling. CONCLUSIONS: This study demonstrates that when given in early onset chronic polyarthritis, oral GCs partially protect against inflammatory bone loss, but induce marked muscle wasting. These results suggest that in patients with inflammatory arthritis receiving GCs, the development of interventions to manage deleterious side effects in muscle should be prioritised.

Spin-charge-lattice coupling in YBaCuFeO5: Optical properties and first-principles calculations.

We combined spectroscopic ellipsometry, Raman scattering spectroscopy, and first-principles calculations to explore the optical properties of YBaCuFeO5 single crystals. Measuring the optical absorption spectrum of YBaCuFeO5 at room temperature revealed a direct optical band gap at approximately 1.41 eV and five bands near 1.69, 2.47, 3.16, 4.26, and 5.54 eV. Based on first-principles calculations, the observed optical excitations were appropriately assigned. Analysis of the temperature dependence of the band gap indicated anomalies in antiferromagnetic phase transition at 455 and 175 K. Additionally, a hardening in the frequency of the Eg phonon mode was observed at 175 K. The value of the spin-phonon coupling constant was 15.7 mRy/Å2. These results suggest a complex nature of spin-charge-lattice interactions in YBaCuFeO5.

Comparison of Two Devices for Intraoperative Portal Venous Flow Measurement in Living-Donor Liver Transplantation: Transit Time Ultrasound and Conventional Doppler Ultrasound.

BACKGROUND: Intraoperative portal venous flow measurement provides surgeons with instant guidance for portal flow modulation during living-donor liver transplantation (LDLT). In this study, we compared the agreement of portal flow measurement obtained by 2 devices: transit time ultrasound (TTU) and conventional Doppler ultrasound (CDU). METHODS: Fifty-four recipients of LDLT underwent intraoperative measurement of portal flow after completion of vascular anastomosis of the implanted partial liver graft. Both TTU and CDU were used concurrently. Agreement of TTU and CDU was assessed by intraclass correlation coefficient using a model of 2-way random effects, absolute agreement, and single measurement. A Bland-Altman plot was applied to assess the variability between the 2 devices. RESULTS: The mean, median, and range of portal venous flow was 1456, 1418, and 117 to 2776 mL/min according to TTU; and 1564, 1566, and 119 to 3216 mL/min according to CDU. The intraclass correlation coefficient of portal venous flow between TTU and CDU was 0.68 (95% confidence interval, 0.51-0.80). The Bland-Altman plots revealed an average variation of 4.8% between TTU and CDU but with a rather wide 95% confidence interval of variation ranging from -57.7% to 67.4%. CONCLUSIONS: Intraoperative TTU and CDU showed moderate agreement in portal flow measurement. However, a relatively wide range of variation exists between TTU and CDU, indicating that data obtained from the 2 devices may not be interchangeable.

Factors associated with treatment delays in pediatric refractory convulsive status epilepticus.

OBJECTIVE: To identify factors associated with treatment delays in pediatric patients with convulsive refractory status epilepticus (rSE). METHODS: This prospective, observational study was performed from June 2011 to March 2017 on pediatric patients (1 month to 21 years of age) with rSE. We evaluated potential factors associated with increased treatment delays in a Cox proportional hazards model. RESULTS: We studied 219 patients (53% males) with a median (25th-75th percentiles [p25-p75]) age of 3.9 (1.2-9.5) years in whom rSE started out of hospital (141 [64.4%]) or in hospital (78 [35.6%]). The median (p25-p75) time from seizure onset to treatment was 16 (5-45) minutes to first benzodiazepine (BZD), 63 (33-146) minutes to first non-BZD antiepileptic drug (AED), and 170 (107-539) minutes to first continuous infusion. Factors associated with more delays to administration of the first BZD were intermittent rSE (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.14-2.09; p = 0.0467) and out-of-hospital rSE onset (HR 1.5, 95% CI 1.11-2.04; p = 0.0467). Factors associated with more delays to administration of the first non-BZD AED were intermittent rSE (HR 1.78, 95% CI 1.32-2.4; p = 0.001) and out-of-hospital rSE onset (HR 2.25, 95% CI 1.67-3.02; p < 0.0001). None of the studied factors were associated with a delayed administration of continuous infusion. CONCLUSION: Intermittent rSE and out-of-hospital rSE onset are independently associated with longer delays to administration of the first BZD and the first non-BZD AED in pediatric rSE. These factors identify potential targets for intervention to reduce time to treatment.

Aberrant expression of microRNAs and the miR-1/MET pathway in canine hepatocellular carcinoma.

Canine hepatocellular carcinoma (HCC) is the most common primary hepatic tumour in dogs. MicroRNA (miRNA) dysregulation has been reported in human HCC and shown to have diagnostic and prognostic value; however, there are no data on miRNA expression in canine HCC. The aim of the present study was to investigate differentially expressed miRNAs in canine HCC. Analysis of miRNA expression in canine HCC tissues and cell lines by quantitative reverse transcription PCR showed that miR-1, miR-122, let-7a, and let-7g were downregulated, whereas miR-10b and miR-21 were upregulated in canine HCC. MET is one of the target genes of miR-1. MET was upregulated in canine HCC at the gene and protein levels, and a significant correlation between the concomitant downregulation of miR-1 and upregulation of MET was observed. Fast/intermediate-proliferating canine HCC cell lines had higher MET gene and protein expression levels than the slow-proliferating cell line. These findings suggest that miRNAs are differentially expressed in canine HCC, and that the miR-1/MET pathway may be associated with canine HCC cell proliferation.

Clinical analysis of NSCLC patients reveals lack of association between EGFR mutation and TET1 downregulation.

Lung cancer is one of the leading causes of death from cancer worldwide, with a poor prognosis in advanced cases. In the past decade, epidermal growth factor receptor (EGFR) inhibitors have shown significant efficacy towards treatment for EGFR mutant lung cancer. Expanding our knowledge of oncogenic EGFR signaling pathways is therefore of highly importance for the cancer field. Recently it has been proposed that mutant EGFR transcriptionally silences the TET1 (ten-eleven translocation methylcytosine dioxygenase 1) gene in cellular and animal models of lung cancer. Since TET1 is a known DNA demethylase, EGFR-mediated TET1 silencing therefore downregulates demethylation of tumor suppressor genes, which then leads to tumor growth inhibition, potentiating the role of TET1 as a tumor suppressor gene in NSCLC. In our study, we examined the role of EGFR-TET1 silencing in NSCLC patient samples. By independently analyzing the TCGA (The Cancer Genome Atlas) NSCLC data set as well as a cohort of patient samples from our hospital and a data set from publicly deposited databases, we did not observe the aforementioned mutant EGFR silencing of TET1. Conversely, in our cohort, TET1 expression levels were significantly elevated in EGFR mutant samples (P=0.007). Patients with higher TET1 levels showed a trend of better response rates to EGFR inhibitors compared to low TET1 staining levels, although the result was not significant (P=0.08). Furthermore, we did not observe a correlation between TET1 expression levels and patient survival. We conclude that while oncogenic EGFR suppression of TET1 is established in cellular and animal models of lung cancer, its role in patient outcome and prognosis remains inconclusive and warrants further investigation.

Rapid Communication: MiR-92a as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk.

Our aim was to identify a suitable microRNA housekeeping gene for real-time PCR analysis of bovine mastitis-related microRNA in milk. We identified , , and as housekeeping gene candidates on the basis of previous Solexa sequencing results. Threshold cycle (CT) values for , , and did not differ between milk from control cows and milk from mastitis-affected cows. NormFinder software identified as the most stable single housekeeping gene. We evaluated the suitability of the housekeeping gene candidates by using them to assess expression levels of the inflammation-related gene . Regardless of the housekeeping gene candidates used for normalization, relative expression levels of were significantly higher in mastitis-affected samples than in control samples. However, of all the housekeeping genes and gene combinations investigated, normalization with alone generated the difference in relative expression between mastitis-affected and control samples with the highest significance. These results suggest that is suitable for use as a housekeeping gene for analysis of bovine mastitis-related microRNA in milk.

Acoustic Radiation Force Impulse Imaging of the Transplant Kidney: Correlation Between Cortical Stiffness and Arterial Resistance in Early Post-transplant Period.

BACKGROUND: Acoustic radiation force impulse (ARFI) imaging is a noninvasive imaging modality for quantitative assessment of tissue stiffness. This study utilized ARFI imaging to assess the stiffness of a transplant renal cortex within the first month after renal transplantation and to explore the correlation between the cortical stiffness and arterial resistance of the transplant kidney. METHODS: Forty renal transplant recipients (male/female = 26/14; mean age: 45.3 years; deceased donor/living related donor = 27/13) were included in this study. ARFI imaging with virtual touch tissue imaging quantification was applied to assess the stiffness of the transplant renal cortex by using a linear ultrasound transducer. Arterial resistance was acquired by spectral Doppler examination of the main artery and intrarenal arteries of the transplant kidney using a curvilinear ultrasound transducer. RESULTS: The stiffness of transplant renal cortex was expressed as shear wave velocity (m/s). The mean value of cortical stiffness was 3.19 ± 1.01 m/s (range: 1.55-5.54). The stiffness of transplant renal cortex was positively correlated with the resistance index of the main renal artery (r = 0.55, P = .001), segmental artery (r = 0.43, P = .005), and interlobar artery (r = 0.42, P = .006). CONCLUSION: The stiffness of a transplant renal cortex is positively correlated with the arterial resistance of the renal transplant in the early post-transplant period. This result indicates that, in addition to renal fibrosis, the stiffness of the transplant renal cortex is also influenced by the hemodynamics of the transplant kidney.

Increased Stiffness of the Remnant Right Lobe Liver After Left Lobectomy or Lateral Segmentectomy in Donors of Living-Donor Liver Transplantation.

BACKGROUND: Liver stiffness is associated with the degree of fibrosis along with other factors. Abrupt change of liver perfusion after hepatectomy is one such factor. In this study, we performed ultrasound elastography to explore the stiffness of the right lobe liver before and after hepatectomy in donors who underwent resection of left lobe or lateral segment of liver. METHODS: A total of 32 left lobe liver donors (18 male and 14 female; age range, 21-55 years; mean age, 35.1 years; 19 left lobectomy with middle hepatic reserved for graft and 13 lateral segmentectomy with middle hepatic vein reserved in the remnant liver) were included in this study. Liver stiffness was measured by means of ultrasound elastography with the use of acoustic radiation force impulse imaging. Stiffness of the right lobe liver was obtained by means of right intercostal approach. RESULTS: The stiffness of remnant right lobe liver significantly increased after hepatectomy (1.24 ± 0.18 vs 1.10 ± 0.13 m/s; P = .001). Donors of left lobe liver showed higher stiffness in the remnant right lobe liver compared with donors of lateral segment (1.30 ± 0.18 vs 1.15 ± 0.14 m/s; P = .027). There was no significant correlation between the remnant right lobe liver stiffness, postoperative liver function, and flow parameters of hepatic artery and portal vein. CONCLUSIONS: The stiffness of remnant liver significantly increased after hepatectomy. Furthermore, the stiffness was higher in donors undergoing left lobectomy compared with those undergoing lateral segmentectomy.

Developing an Integrated Modeling Tool for River Water Quality Index Assessment.

The goal of this study was to establish a modeling tool for river water quality with a direct linkage to the water quality index (WQI5) calculation and the river water quality model, the Water Quality Analysis Simulation Program (WASP), for pollutant transport modeling. The integrated WASP and WQI5 tool was field-tested to assess pollutant loadings and their impacts on river environment. Suspended solid (SS) and electric conductivity (EC) correlation equations and the WQI5 calculation tool were included in the water quality model and direct WQI5 calculation. The SS concentration, which was influenced by river flows, had crucial effects on river water quality and WQI5 values. EC value was controlled by dissolution of soil minerals, which was affected by the watershed drainage area and surface runoff. The integrated system could establish a direct correlation for river water quality, river flow, and WQI5.

Vitiligo and depression: a systematic review and meta-analysis of observational studies.

Vitiligo is a common depigmenting disorder with profound psychosocial impacts. Previous observational studies have suggested a link between vitiligo and psychiatric morbidity, such as depression. However, variability in study design makes it difficult to quantify accurately the relationship between vitiligo and depression. We aimed to investigate the underlying prevalence and risk of depression among patients with vitiligo. A comprehensive search of MEDLINE, Embase and the Cochrane Library was conducted. Cross-sectional, case-control or cohort studies that assessed the prevalence of depression among patients with vitiligo or the relationship between vitiligo and depression were included. DerSimonian and Laird random-effects models were utilized to calculate the pooled prevalence and relative risks. Publication bias was evaluated by funnel plots and Egger's tests. Twenty-five studies with 2708 cases of vitiligo were included. Based on diagnostic codes, the pooled prevalence of depression among patients with vitiligo was 0·253 [95% confidence interval (CI) 0·16-0·34; P < 0·001)]. Using self-reported questionnaires, the pooled prevalence of depressive symptoms was 0·336 (95% CI 0·25-0·42; P < 0·001). The pooled odds ratio of depression among patients with vitiligo was 5·05 vs. controls (95% CI 2·21-11·51; P < 0·001). Moderate-to-high heterogeneity was observed between the studies. Patients with vitiligo were significantly more likely to suffer from depression. Clinical depression or depressive symptoms can be prevalent, with the actual prevalence differing depending on screening instruments or, possibly, geographical regions. Clinicians should actively evaluate patients with vitiligo for signs/symptoms of depression and provide appropriate referrals to manage their psychiatric symptoms accordingly.

Bullous pemphigoid and its association with neurological diseases: a systematic review and meta-analysis.

Bullous pemphigoid (BP) is a chronic, autoimmune vesiculobullous disease that frequently occurs in the elderly population. Previous epidemiological studies have suggested an association between BP and neurological diseases; some studies, however, showed conflicting results. This study aimed to investigate if patients with BP have significantly higher risks for neurological disorders, compared to controls. A comprehensive search was performed using MEDLINE, EMBASE and Cochrane library databases. Case-control and cohort studies that assessed the relationship between BP and neurological diseases were included. DerSimonian and Laird random-effects models were utilized to calculate the pooled relative risks (RRs). Publication bias was evaluated qualitatively by constructing a funnel plot and quantitatively by conducting Egger's test. Fourteen studies, with 23 369 BP cases and 128 697 controls were included in this meta-analysis. Patients with BP were significantly more likely to have stroke (RR 2.68, 95% CI: 2.07-3.46), Parkinson's disease (PD; RR 3.42, 95% CI: 3.01-3.87), dementia (RR 4.46, 95% CI: 3.23-6.16), epilepsy (RR 2.98, 95% CI: 1.42-6.28), multiple sclerosis (RR 12.40, 95% CI: 6.64-23.17) and any aforementioned neurological disease (RR 4.93, 95% CI: 3.62-6.70), compared to controls. Moderate to high heterogeneity were observed for analyses of most neurological diseases, except for PD and multiple sclerosis. This study provided support for a significant association between BP and neurological diseases. Clinicians should be aware of this association and manage modifiable risk factors for neurological diseases accordingly.

AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B.

Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the Vmax of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.

Psoriasis and uric acid: a population-based cross-sectional study.

BACKGROUND: Psoriasis has been reported to be associated with raised serum uric acid levels and gout, and uric acid has been demonstrated to mediate inflammatory pathways via secretion of pro-inflammatory chemokines. AIM: To evaluate the association between psoriasis, serum uric acid levels and gout in a cross-sectional study using the US National Health and Nutrition Examination Survey (NHANES) database. METHODS: Data on clinical history of psoriasis, gout and other relevant medical conditions from the questionnaire as well as laboratory parameters for serum uric acid and lipid levels in the periods 2003-2006 and 2011-2012 were analysed. Multivariate analysis with logistic regression modelling was performed, with hyperuricaemia as the dependent variable, and age, sex, ethnicity, body mass index, metabolic syndrome, current smoking status, alcohol consumption and history of psoriasis as the independent variables. RESULTS: Of the 11 282 study participants, 297 (2.6%) reported a history of psoriasis and 1493 (13.2%) were found to have hyperuricaemia. Patients with psoriasis were at increased risk of having hyperuricaemia, compared with those without psoriasis (OR = 1.37; P = 0.04). They were also more likely to report a history of gout (OR = 1.83; P < 0.05). However, neither association was significant after adjusting for potential confounders with multivariate logistic regression. CONCLUSION: In conclusion, there was insufficient evidence to show that psoriasis is an independent risk factor of hyperuricaemia or gout. A raised serum uric acid level may be a consequence of metabolic syndrome, which in turn is associated with psoriasis.

Macrophage migration inhibitory factor has a permissive role in concanavalin A-induced cell death of human hepatoma cells through autophagy.

Concanavalin A (ConA) is a lectin and T-cell mitogen that can activate immune responses. In recent times, ConA-induced cell death of hepatoma cells through autophagy has been reported and its therapeutic effect was confirmed in a murine in situ hepatoma model. However, the molecular mechanism of ConA-induced autophagy is still unclear. As macrophage migration inhibitory factor (MIF), which is a proinflammatory cytokine, can trigger autophagy in human hepatoma cells, the possible involvement of MIF in ConA-induced autophagy was investigated in this study. We demonstrated that cell death is followed by an increment in MIF expression and secretion in the ConA-stimulated human hepatoma cell lines, HuH-7 and Hep G2. In addition, ConA-induced autophagy and cell death of hepatoma cells were blocked in the presence of an MIF inhibitor. Knockdown of endogenous MIF by small hairpin RNA confirmed that MIF is required for both ConA-induced autophagy and death of hepatoma cells. Furthermore, signal pathway studies demonstrated that ConA induces signal transducer and activator of transcription 3 (STAT3) phosphorylation to trigger MIF upregulation, which in turn promotes Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-dependent autophagy. By using a murine in situ hepatoma model, we further demonstrated that MIF contributes to anti-hepatoma activity of ConA by regulating STAT3-MIF-BNIP3-dependent autophagy. In summary, our findings uncover a novel role of MIF in lectin-mediated anti-hepatoma activities by regulating autophagy.

Effective NET formation in neutrophils from individuals with G6PD Taiwan-Hakka is associated with enhanced NADP(+) biosynthesis.

In response to infection, neutrophils employ various strategies to defend against the invading microbes. One of such defense mechanisms is the formation of neutrophil extracellular traps (NETs). Recent studies suggest that reactive oxygen species is a signal critical to NET formation. This prompts us to examine whether neutrophils from individuals with glucose-6-phosphate dehydrogenase (G6PD) Taiwan-Hakka variant, which are prone to oxidative stress generation, have altered ability to form NET. We adopted an image-based method to study the NET formation potential in neutrophils from G6PD-deficient patients. Neutrophils from either normal or G6PD-deficient individuals underwent NETosis in response to phorbol 12-myristate 13-acetate (PMA). The extent of NETosis in the former did not significantly differ from that of the latter. Diphenyleneiodonium sulfate (DPI) and 3-methyladenine (MA) inhibited PMA-stimulated NET formation in these cells, suggesting the involvement of NADPH oxidase and autophagy in the process. Glucose oxidase (GO) and xanthine oxidase/xanthine (XO/X) could induce a similar extent of NET formation in normal and G6PD-deficient neutrophils. GO- or XO-induced NETosis was not inhibitable by MA, implying that reactive oxygen species (ROS) can act as an independent signal for activation of NETosis. Mechanistically, enhanced superoxide production in neutrophils was associated with increases in levels of NAD(+) and NADP(+), as well as activation of NAD(+) kinase. Taken together, these findings suggest that G6PD-deficient neutrophils are as equally efficient as normal cells in NET formation, and their deficiency in G6PD-associated NADPH regeneration capacity is largely compensated for by nicotinamide nucleotide biosynthesis.