Gender trends in authorships and publication impact in Academic Radiology—a 10-year perspective

Objectives: To analyze the development of publication numbers of female authors in high-, medium-, and low-impact radiological journals. Methods: In this bibliometric analysis, gender of the first (FA) and senior author (SA) was assigned to all original research articles and reviews, published in 10 high-, medium-, and low-impact radiological journals in 2007/8 and 2017/18. The adjusted event rate (AER) and adjusted odds ratio (AOR) were calculated using mixed logistic and multinomial logistic regression models to assess and compare female publications according to impact factor, journal, author position, and combination. Results: The proportion of female FA and female SA in N = 6979 (2007/2008) and N = 7383 (2017/2018) articles increased to 29.1% and 16.1% in 2017/2018, respectively. While most female authorships were continuously observed in medium-impact journals, the strongest increase occurred for both female FA (AOR 2.0; p < .0001) and SA (AOR 2.1; p < .0001) in low-impact journals. Female SA published significantly more often in a low- (AOR 1.5) or medium- (AOR 1.8) than in a high-ranking journal. Among the high-ranking journals, female FA published most frequently in European Radiology (32.4%; 95% CI [29.3-35.8]; p < .0001), female SA in Investigative Radiology (15.9%; 95% CI [13.7-18.4]; p < .0001). Male same-sex authorships decreased (AOR 0.9), but remained at least twice as common as all-female or mixed authorships. Conclusion: The increase in female authorship is reflected in all impact areas. Female FA and SA increased most in low-ranking journals but are most common in medium-ranking journals. Female SA remain rare, especially in high impact journals

Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance

OBJECTIVE: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. METHODS: The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1(Cre)-Abcb10(flox/flox)). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. RESULTS: Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H(2)O(2)-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H(2)O(2) and GSIS, which was reversed by bilirubin treatments. CONCLUSIONS: Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia

Gender trends in authorships and publication impact in Academic Radiology—a 10-year perspective

Objectives!#!To analyze the development of publication numbers of female authors in high-, medium-, and low-impact radiological journals.!##!Methods!#!In this bibliometric analysis, gender of the first (FA) and senior author (SA) was assigned to all original research articles and reviews, published in 10 high-, medium-, and low-impact radiological journals in 2007/8 and 2017/18. The adjusted event rate (AER) and adjusted odds ratio (AOR) were calculated using mixed logistic and multinomial logistic regression models to assess and compare female publications according to impact factor, journal, author position, and combination.!##!Results!#!The proportion of female FA and female SA in N = 6979 (2007/2008) and N = 7383 (2017/2018) articles increased to 29.1% and 16.1% in 2017/2018, respectively. While most female authorships were continuously observed in medium-impact journals, the strongest increase occurred for both female FA (AOR 2.0; p &amp;lt; .0001) and SA (AOR 2.1; p &amp;lt; .0001) in low-impact journals. Female SA published significantly more often in a low- (AOR 1.5) or medium- (AOR 1.8) than in a high-ranking journal. Among the high-ranking journals, female FA published most frequently in European Radiology (32.4%; 95% CI [29.3-35.8]; p &amp;lt; .0001), female SA in Investigative Radiology (15.9%; 95% CI [13.7-18.4]; p &amp;lt; .0001). Male same-sex authorships decreased (AOR 0.9), but remained at least twice as common as all-female or mixed authorships.!##!Conclusion!#!The increase in female authorship is reflected in all impact areas. Female FA and SA increased most in low-ranking journals but are most common in medium-ranking journals. Female SA remain rare, especially in high impact journals.!##!Key points!#!• Compared to the proportion of female radiologists worldwide, female senior authors are underrepresented in all impact areas, in particular in high-impact journals. • Among the included high-ranking radiological journals, female first authors and senior authors were strongest represented in European Radiology and Investigative Radiology, while across all impact areas they mostly published in medium-ranking journals. • Female author combinations were more frequent in low- and medium- than in high-ranking journals, whereas male author combinations remained more common than female senior author collaborations in all impact areas

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria.

Recent breakthroughs in live-cell imaging have enabled visualization of cristae, making it feasible to investigate the structure-function relationship of cristae in real time. However, quantifying live-cell images of cristae in an unbiased way remains challenging. Here, we present a novel, semi-automated approach to quantify cristae, using the machine-learning Trainable Weka Segmentation tool. Compared with standard techniques, our approach not only avoids the bias associated with manual thresholding but more efficiently segments cristae from Airyscan and structured illumination microscopy images. Using a cardiolipin-deficient cell line, as well as FCCP, we show that our approach is sufficiently sensitive to detect perturbations in cristae density, size, and shape. This approach, moreover, reveals that cristae are not uniformly distributed within the mitochondrion, and sites of mitochondrial fission are localized to areas of decreased cristae density. After a fusion event, individual cristae from the two mitochondria, at the site of fusion, merge into one object with distinct architectural values. Overall, our study shows that machine learning represents a compelling new strategy for quantifying cristae in living cells

Quantification of cristae architecture reveals time-dependent characteristics of individual mitochondria.

Recent breakthroughs in live-cell imaging have enabled visualization of cristae, making it feasible to investigate the structure-function relationship of cristae in real time. However, quantifying live-cell images of cristae in an unbiased way remains challenging. Here, we present a novel, semi-automated approach to quantify cristae, using the machine-learning Trainable Weka Segmentation tool. Compared with standard techniques, our approach not only avoids the bias associated with manual thresholding but more efficiently segments cristae from Airyscan and structured illumination microscopy images. Using a cardiolipin-deficient cell line, as well as FCCP, we show that our approach is sufficiently sensitive to detect perturbations in cristae density, size, and shape. This approach, moreover, reveals that cristae are not uniformly distributed within the mitochondrion, and sites of mitochondrial fission are localized to areas of decreased cristae density. After a fusion event, individual cristae from the two mitochondria, at the site of fusion, merge into one object with distinct architectural values. Overall, our study shows that machine learning represents a compelling new strategy for quantifying cristae in living cells

Individual islet respirometry reveals functional diversity within the islet population of mice and human donors

Objective: Islets from the same pancreas show remarkable variability in glucose sensitivity. While mitochondrial respiration is essential for glucose-stimulated insulin secretion, little is known regarding heterogeneity in mitochondrial function at the individual islet level. This is due in part to a lack of high-throughput and non-invasive methods for detecting single islet function. Methods: We have developed a novel non-invasive, high-throughput methodology capable of assessing mitochondrial respiration in large-sized individual islets using the XF96 analyzer (Agilent Technologies). Results: By increasing measurement sensitivity, we have reduced the minimal size of mouse and human islets needed to assess mitochondrial respiration to single large islets of >35,000 μm2 area (∼210 μm diameter). In addition, we have measured heterogeneous glucose-stimulated mitochondrial respiration among individual human and mouse islets from the same pancreas, allowing population analyses of islet mitochondrial function for the first time. Conclusions: We have developed a novel methodology capable of analyzing mitochondrial function in large-sized individual islets. By highlighting islet functional heterogeneity, we hope this methodology can significantly advance islet research. Keywords: Islets, Mitochondria, Respirometry, Glucos

Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance

ObjectiveThe contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown.MethodsThe expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets.ResultsCarrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments.ConclusionsBeta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia

ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases

AMPK Regulates ER Morphology and Function in Stressed Pancreatic β-Cells via Phosphorylation of DRP1

Experimental lipotoxicity constitutes a model for β-cell demise induced by metabolic stress in obesity and type 2 diabetes. Fatty acid excess induces endoplasmic reticulum (ER) stress, which is accompanied by ER morphological changes whose mechanisms and relevance are unknown. We found that the GTPase dynamin-related protein 1 (DRP1), a key regulator of mitochondrial fission, is an ER resident regulating ER morphology in stressed β-cells. Inhibition of DRP1 activity using a GTP hydrolysis-defective mutant (Ad-K38A) attenuated fatty acid-induced ER expansion and mitochondrial fission. Strikingly, stimulating the key energy-sensor AMP-activated protein kinase (AMPK) increased the phosphorylation at the anti-fission site Serine 637 and largely prevented the alterations in ER and mitochondrial morphology. Expression of a DRP1 mutant resistant to phosphorylation at this position partially prevented the recovery of ER and mitochondrial morphology by AMPK. Fatty acid-induced ER enlargement was associated with proinsulin retention in the ER, together with increased proinsulin/insulin ratio. Stimulation of AMPK prevented these alterations, as well as mitochondrial fragmentation and apoptosis. In summary, DRP1 regulation by AMPK delineates a novel pathway controlling ER and mitochondrial morphology, thereby modulating the response of β-cells to metabolic stress. DRP1 may thus function as a node integrating signals from stress regulators, such as AMPK, to coordinate organelle shape and function