Adipose Kiss1 controls aerobic exercise-related adaptive responses in adipose tissue energy homeostasis.

Kisspeptin signaling regulates energy homeostasis. Adiposity is the principal source and receiver of peripheral Kisspeptin, and adipose Kiss1 metastasis suppressor (Kiss1) gene expression is stimulated by exercise. However, whether the adipose Kiss1 gene regulates energy homeostasis and plays a role in adaptive alterations during prolonged exercise remains unknown. Here, we investigated the role of Kiss1 role in mice and adipose tissues and the adaptive changes it induces after exercise, using adipose-specific Kiss1 knockout (Kiss1adipoq-/-) and adeno-associated virus-induced adipose tissue Kiss1-overexpressing (Kiss1adipoq over) mice. We found that adipose-derived kisspeptin signal regulates lipid and glucose homeostasis to maintain systemic energy homeostasis, but in a sex-dependent manner, with more pronounced metabolic changes in female mice. Kiss1 regulated adaptive alterations of genes and proteins in tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) pathways in female gWAT following prolonged aerobic exercise. We could further show that adipose Kiss1 deficiency leads to reduced peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α) protein content of soleus muscle and maximum oxygen uptake (VO2 max) of female mice after prolonged exercise. Therefore, adipose Kisspeptin may be a novel adipokine that increases organ sensitivity to glucose, lipids, and oxygen following exercise.

Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers.

Long-term exposure to peroxisome proliferator-activated receptor γ (PPARγ) agonists such as rosiglitazone induces browning of rodent and human adipocytes; however, the transcriptional mechanisms governing this phenotypic switch in adipocytes are largely unknown. Here we show that rosiglitazone-induced browning of human adipocytes activates a comprehensive gene program that leads to increased mitochondrial oxidative capacity. Once induced, this gene program and oxidative capacity are maintained independently of rosiglitazone, suggesting that additional browning factors are activated. Browning triggers reprogramming of PPARγ binding, leading to the formation of PPARγ "superenhancers" that are selective for brown-in-white (brite) adipocytes. These are highly associated with key brite-selective genes. Based on such an association, we identified an evolutionarily conserved metabolic regulator, Kruppel-like factor 11 (KLF11), as a novel browning transcription factor in human adipocytes that is required for rosiglitazone-induced browning, including the increase in mitochondrial oxidative capacity. KLF11 is directly induced by PPARγ and appears to cooperate with PPARγ in a feed-forward manner to activate and maintain the brite-selective gene program.

Integrated analysis of motif activity and gene expression changes of transcription factors.

The ability to predict transcription factors based on sequence information in regulatory elements is a key step in systems-level investigation of transcriptional regulation. Here, we have developed a novel tool, IMAGE, for precise prediction of causal transcription factors based on transcriptome profiling and genome-wide maps of enhancer activity. High precision is obtained by combining a near-complete database of position weight matrices (PWMs), generated by compiling public databases and systematic prediction of PWMs for uncharacterized transcription factors, with a state-of-the-art method for PWM scoring and a novel machine learning strategy, based on both enhancers and promoters, to predict the contribution of motifs to transcriptional activity. We applied IMAGE to published data obtained during 3T3-L1 adipocyte differentiation and showed that IMAGE predicts causal transcriptional regulators of this process with higher confidence than existing methods. Furthermore, we generated genome-wide maps of enhancer activity and transcripts during human mesenchymal stem cell commitment and adipocyte differentiation and used IMAGE to identify positive and negative transcriptional regulators of this process. Collectively, our results demonstrate that IMAGE is a powerful and precise method for prediction of regulators of gene expression.

Molecular Nanowire Bonding to Epitaxial Single-Layer MoS2 by an On-Surface Ullmann Coupling Reaction.

Lateral heterostructures consisting of 2D transition metal dichalcogenides (TMDCs) directly interfaced with molecular networks or nanowires can be used to construct new hybrid materials with interesting electronic and spintronic properties. However, chemical methods for selective and controllable bond formation between 2D materials and organic molecular networks need to be developed. As a demonstration of a self-assembled organic nanowire-TMDC system, a method to link and interconnect epitaxial single-layer MoS2 flakes with organic molecules is demonstrated. Whereas pristine epitaxial single-layer MoS2 has no affinity for molecular attachment, it is found that single-layer MoS2 will selectively bind the organic molecule 2,8-dibromodibenzothiophene (DBDBT) in a surface-assisted Ullmann coupling reaction when the MoS2 has been activated by pre-exposing it to hydrogen. Atom-resolved scanning tunneling microscopy (STM) imaging is used to analyze the bonding of the nanowires, and thereby it is revealed that selective bonding takes place on a specific S atom at the corner site between the two types of zig-zag edges available in a hexagonal single layer MoS2 sheet. The method reported here successfully combining synthesis of epitaxial TMDCs and Ullmann coupling reactions on surfaces may open up new synthesis routes for 2D organic-TMDC hybrid materials.

Chair Versus Chairman: Does Orthopaedics Use the Gendered Term More Than Other Specialties?

BACKGROUND: Orthopaedics is the least gender-diverse medical specialty. Research suggests that the use of gendered language can contribute to workforce disparity and that gender-neutral language supports the inclusion and advancement of women, but the degree to which gender-neutral language is used by academic departments in what typically is a department's highest position (department chair) has not been characterized. QUESTIONS/PURPOSES: (1) Is the proportion of department websites that use the term chairman (as opposed to chair) greater in orthopaedics than in five other surgical and medical specialties? (2) Are departments led by chairs who are women less likely to use "chairman" than those led by men, and does this vary by specialty? METHODS: Seven hundred fourteen official websites of orthopaedic, neurosurgery, general surgery, internal medicine, pediatrics, and obstetrics and gynecology departments affiliated with 129 allopathic medical schools were screened. Any use of the term chairman on title pages, welcome messages, and faculty profile pages was identified using a Boyer-Moore string-search algorithm and terms were classified based on their location on the site. The overall use of the term chairman was compared by specialty and gender of the chair. RESULTS: Sixty percent of orthopaedic department websites (71 of 119) used the term chairman at least once, a proportion higher than that of pediatrics (36% [46 of 128]; OR 0.38; 95% CI, 0.23 to 0.63; p < 0.001), internal medicine (31% [38 of 122]; OR 0.030; 95% CI, 0.18 to 0.53; p < 0.001), and obstetrics and gynecology (29% [37 of 126]; OR 0.28; 95% CI, 0.17 to 0.48; p < 0.001), but no different than that of neurosurgery (57% [54 of 94]; OR 0.91; 95% CI, 0.52 to 1.6; p = 0.74) and general surgery (55% [69 of 125]; OR 0.83; 95% CI, 0.50 to 1.4; p = 0.48). Across disciplines, departments whose chairs were women were much less likely to use the term chairman than departments whose chairs were men (14% [17 of 122] versus 50% [297 of 592]; OR 0.16; 95% CI, 0.09 to 0.28; p < 0.001). CONCLUSIONS: The frequent use of the term chairman in orthopaedics, coupled with the preference of women to use the term chair, suggests considerable room for growth in the use of gender-equal language in orthopaedics. CLINICAL RELEVANCE: Our current efforts to increase the number of women in orthopaedics may be undermined by gendered language, which can create and reinforce gendered culture in the field. Electing to use gender-neutral leadership titles, while a relatively small step in the pursuit of a more gender-equal environment, presents an immediate and no-cost way to support a more inclusive culture and counteract unconscious gender bias. Future studies should explore the individual attitudes of chairs regarding the use of gendered titles and identify additional ways in which biases may manifest; for example, the use of gendered language in interpersonal communications and the presence of unconscious bias in leadership evaluations. Continued efforts to understand implicit bias in orthopaedics can guide actionable strategies for counteracting gendered stereotypes of the specialty, in turn aiding initiatives to recruit and promote women in the field.

Long-range symmetry breaking in embedded ferroelectrics.

The characteristic functionality of ferroelectric materials is due to the symmetry of their crystalline structure. As such, ferroelectrics lend themselves to design approaches that manipulate this structural symmetry by introducing extrinsic strain. Using in situ dark-field X-ray microscopy to map lattice distortions around deeply embedded domain walls and grain boundaries in BaTiO3, we reveal that symmetry-breaking strain fields extend up to several micrometres from domain walls. As this exceeds the average domain width, no part of the material is elastically relaxed, and symmetry is universally broken. Such extrinsic strains are pivotal in defining the local properties and self-organization of embedded domain walls, and must be accounted for by emerging computational approaches to material design.

The KDM5 family is required for activation of pro-proliferative cell cycle genes during adipocyte differentiation.

The KDM5 family of histone demethylases removes the H3K4 tri-methylation (H3K4me3) mark frequently found at promoter regions of actively transcribed genes and is therefore generally considered to contribute to corepression. In this study, we show that knockdown (KD) of all expressed members of the KDM5 family in white and brown preadipocytes leads to deregulated gene expression and blocks differentiation to mature adipocytes. KDM5 KD leads to a considerable increase in H3K4me3 at promoter regions; however, these changes in H3K4me3 have a limited effect on gene expression per se. By contrast, genome-wide analyses demonstrate that KDM5A is strongly enriched at KDM5-activated promoters, which generally have high levels of H3K4me3 and are associated with highly expressed genes. We show that KDM5-activated genes include a large set of cell cycle regulators and that the KDM5s are necessary for mitotic clonal expansion in 3T3-L1 cells, indicating that KDM5 KD may interfere with differentiation in part by impairing proliferation. Notably, the demethylase activity of KDM5A is required for activation of at least a subset of pro-proliferative cell cycle genes. In conclusion, the KDM5 family acts as dual modulators of gene expression in preadipocytes and is required for early stage differentiation and activation of pro-proliferative cell cycle genes.

Direct observation of grain rotations during coarsening of a semisolid Al-Cu alloy.

Sintering is a key technology for processing ceramic and metallic powders into solid objects of complex geometry, particularly in the burgeoning field of energy storage materials. The modeling of sintering processes, however, has not kept pace with applications. Conventional models, which assume ideal arrangements of constituent powders while ignoring their underlying crystallinity, achieve at best a qualitative description of the rearrangement, densification, and coarsening of powder compacts during thermal processing. Treating a semisolid Al-Cu alloy as a model system for late-stage sintering-during which densification plays a subordinate role to coarsening-we have used 3D X-ray diffraction microscopy to track the changes in sample microstructure induced by annealing. The results establish the occurrence of significant particle rotations, driven in part by the dependence of boundary energy on crystallographic misorientation. Evidently, a comprehensive model for sintering must incorporate crystallographic parameters into the thermodynamic driving forces governing microstructural evolution.

Gene program-specific regulation of PGC-1{alpha} activity.

Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1 α (PGC-1α) activation coordinates induction of the hepatic fasting response through coactivation of numerous transcription factors and gene programs. In the June 15, 2011, issue of Genes & Development, Lustig and colleagues (pp. 1232-1244) demonstrated that phosphorylation of PGC-1α by the p70 ribosomal protein S6 kinase 1 (S6K1) specifically interfered with the interaction between PGC-1α and HNF4α in liver and blocked the coactivation of the gluconeogenic target genes. This demonstrates how independent fine-tuning of gene programs coregulated by the same coactivator can be obtained.

Acute TNF-induced repression of cell identity genes is mediated by NFκB-directed redistribution of cofactors from super-enhancers.

The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in low-grade adipose tissue inflammation and development of insulin resistance during obesity. In this context, nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) is directly involved and required for the acute activation of the inflammatory gene program. Here, we show that the major transactivating subunit of NFκB, v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), is also required for acute TNF-induced suppression of adipocyte genes. Notably, this repression does not involve RELA binding to the associated enhancers but rather loss of cofactors and enhancer RNA (eRNA) selectively from high-occupancy sites within super-enhancers. Based on these data, we have developed models that, with high accuracy, predict which enhancers and genes are repressed by TNF in adipocytes. We show that these models are applicable to other cell types where TNF represses genes associated with super-enhancers in a highly cell-type-specific manner. Our results propose a novel paradigm for NFκB-mediated repression, whereby NFκB selectively redistributes cofactors from high-occupancy enhancers, thereby specifically repressing super-enhancer-associated cell identity genes.

Cofactor squelching: Artifact or fact?

Cofactor squelching is the term used to describe competition between transcription factors (TFs) for a limited amount of cofactors in a cell with the functional consequence that TFs in a given cell interfere with the activity of each other. Since cofactor squelching was proposed based primarily on reporter assays some 30 years ago, it has remained controversial, and the idea that it could be a physiologically relevant mechanism for transcriptional repression has not received much support. However, recent genome-wide studies have demonstrated that signal-dependent TFs are very often absent from the enhancers that are acutely repressed by those signals, which is consistent with an indirect mechanism of repression such as squelching. Here we review these recent studies in the light of the classical studies of cofactor squelching, and we discuss how TF cooperativity in so-called hotspots and super-enhancers may sensitize these to cofactor squelching.

Noninvasive characterization of optical fibers.

Capillary optical fibers with hole diameters of several micrometers are important for novel plasmonic applications and medical diagnosis. In order to ensure the optical functionality of these fibers, the diameter of the capillary hole needs to be realized with high accuracy. Here, we introduce a novel and noninvasive methodology to characterize optical fibers and discuss it for the assessment of capillaries. In this method, the fiber is side-illuminated by a coherent beam, and the resulting diffraction pattern is analyzed. This corresponds to an in-line holographic measurement in the presence of strong scattering. A numerical parameter retrieval allows us to characterize the capillary hole diameter with an accuracy of approximately 100 nm for radii between several hundreds of nanometers and several tens of micrometers.

Attention-Deficit/Hyperactivity Disorder Symptoms and Life Satisfaction in a Representative Adolescent and Adult Sample.

Although it is well documented that attention-deficit/hyperactivity disorder (ADHD) is associated with reduced life satisfaction, the mechanisms that might explain this co-occurrence are unclear. We examined the correlation of ADHD symptoms with life satisfaction and whether this association is mediated by (lacking) social support and depressive symptoms. Self-reported ADHD symptoms, life satisfaction, social support, and depressive symptoms were assessed in a representative, predominantly adult sample from the general population (14-91 years, N = 2517). Attention-deficit/hyperactivity disorder symptoms correlated negatively with life satisfaction (r = -0.41, p < 0.01), even after demographic factors (gender, age, income) and common risk factors (not being in a relationship, being unemployed) were controlled for (r = -0.39, p < 0.01). Social support mediated up to 23% and depressive symptoms up to 44% in the association between ADHD symptoms and life satisfaction. Counteracting problems with social relationships and treating depressive symptoms may help to increase life satisfaction in adults with ADHD symptoms.

iRNA-seq: computational method for genome-wide assessment of acute transcriptional regulation from total RNA-seq data.

RNA-seq is a sensitive and accurate technique to compare steady-state levels of RNA between different cellular states. However, as it does not provide an account of transcriptional activity per se, other technologies are needed to more precisely determine acute transcriptional responses. Here, we have developed an easy, sensitive and accurate novel computational method, IRNA-SEQ: , for genome-wide assessment of transcriptional activity based on analysis of intron coverage from total RNA-seq data. Comparison of the results derived from iRNA-seq analyses with parallel results derived using current methods for genome-wide determination of transcriptional activity, i.e. global run-on (GRO)-seq and RNA polymerase II (RNAPII) ChIP-seq, demonstrate that iRNA-seq provides similar results in terms of number of regulated genes and their fold change. However, unlike the current methods that are all very labor-intensive and demanding in terms of sample material and technologies, iRNA-seq is cheap and easy and requires very little sample material. In conclusion, iRNA-seq offers an attractive novel alternative to current methods for determination of changes in transcriptional activity at a genome-wide level.

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and ß-cell protection.

Type 1 diabetes is due to destruction of pancreatic ß-cells. Lysine deacetylase inhibitors (KDACi) protect ß-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing ß-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1ß + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.

[Coping Process in Women with FGM from Ethiopia - The Contribution of Attitude]. / Belastungsbewältigung bei Frauen mit FGM aus Äthiopien ­ Zur Rolle der Einstellung.

The Female Genital Mutilation (FGM) is still practiced in many countries and mainly performed for traditional reasons. In this study, the relationship of the FGM type (type I and type III) with anxiety, depression, and posttraumatic stress disorder as well as the attitude toward FGM was analyzed. For this purpose the data of N=109 of FGM type I and III affected women from Ethiopia were collected. Analyses show moderation effects. It was found that the symptoms of depression and PTSD were less pronounced with a positive attitude towards the FGM in the sample of severely mutilated women (type III). It seems that the attitude toward FGM plays a major role in enhancing social recognition of those affected, thus better coping can take place. As well, this study shows the importance of the attitude of FGM tradition in the population to protect young girls prone for FGM.

Phase-contrast neutron imaging compared with wave propagation and McStas simulations.

Propagation-based phase contrast, for example in the form of edge enhancement contrast, is well established within X-ray imaging but is not widely used in neutron imaging. This technique can help increase the contrast of low-attenuation samples but may confuse quantitative absorption measurements. Therefore, it is important to understand the experimental parameters that cause and amplify or dampen this effect in order to optimize future experiments properly. Two simulation approaches have been investigated, a wave-based simulation and a particle-based simulation conducted in McStas [Willendrup & Lefmann (2020). J. Neutron Res. 22, 1-16], and they are compared with experimental data. The experiment was done on a sample of metal foils with weakly and strongly neutron absorbing layers, which were measured while varying the rotation angle and propagation distance from the sample. The experimental data show multiple signals: attenuation, phase contrast and reflection. The wave model reproduces the sample attenuation and the phase peaks but it does not reproduce the behavior of these peaks as a function of rotation angle. The McStas simulation agrees better with the experimental data, as it reproduces attenuation, phase peaks and reflection, as well as the change in these signals as a function of rotation angle and distance. This suggests that the McStas simulation approach, where the particle description of the neutron facilitates the incorporation of multiple effects, is the most convenient way of modeling edge enhancement in neutron imaging.

[Cognitive, linguistic, motoric, and social deficits in schoolstarters with behavioral disorders]. / Kognitive, sprachliche, motorische und sozial-emotionale Defizite bei verhaltensauffälligen Schulanfängern.

Studies show that ADHD, conduct disorders, and anxiety disorders are clinical disorders mostly diagnosed in schoolstarters. The preschool medical examination in Bremen was therefore extended by behavioral screenings. Based on their screening results from the SEU (health examination for school entry) 2011 in Bremen, 67 preschoolers were tested for behavioral disorders. Subsequently, children with behavioral or emotional symptoms (N = 56) were compared to symptomfree controls (N = 52) for their cognitive, motoric, linguistic, and social-emotional development. Psychosocial health was obtained through external assessment by the parents and kindergarten teachers. Results of the WPPSI-III, M-ABC-2, and ET 6-6 were included in the analysis. 32 children met the criteria for behavioral disorders. Children with behavioral or emotional symptoms showed significant lower scores on tests measuring cognitive, motoric, linguistic and emotional development compared to controls. Results suggest that there is necessity to screen all preschoolers for behavioral disorders before entering school. Because children with clinical or subclinical behavioral disorders showed major developmental deficits compared to children without behavioral symptoms, it is essential to conduct a multiple assessment on children with suspected behavioral disorders to ensure early developmental support and adequate interventional programs.

[Diagnostic of ADHD in childhood and adolescence with the K-SADS-PL]. / Diagnostik der ADHS im Kindes- und Jugendalter mit dem K-SADS-PL.

Attention Deficit-/Hyperactivity Disorder (ADHD) is one of the most prevalent psychiatric disorders in childhood and adolescence, often accompanied by comorbid disorders. A high standard of diagnostic assessment combined with a demand for valid diagnostic instruments is necessary. The K-SADS-PL is an established semi-structured interview, focusing on the categorical assessment of psychiatric disorders. The aim of the following study was to examine specific characteristics of ADHD symptomatology including functional and behavioral assessment. Therefore correlations between the result in a diagnostic interview (K-SADS-PL) and different ADHD-specific instruments were performed. Groups were formed (exposed vs. unexposed), based on the diagnostic finding in the K-SADS-PL. Group-specific test score differences were calculated and compared by multivariate analyses of covariance. Children with ADHD showed a significantly higher impact of conduct and emotional problems than the unexposed group. Health related quality of life was more impaired in children and families suffering from ADHD which refers to the relevance of family-oriented psychotherapy.

3D microscopy at the nanoscale reveals unexpected lattice rotations in deformed nickel.

In polycrystalline metals, plastic deformation is accompanied by lattice rotations resulting from dislocation glide. Following these rotations in three dimensions requires nondestructive methods that so far have been limited to grain sizes at the micrometer scale. We tracked the rotations of individual grains in nanograined nickel by using three-dimensional orientation mapping in a transmission electron microscope before and after in situ nanomechanical testing. Many of the larger-size grains underwent unexpected lattice rotations, which we attributed to a reversal of rotation during unloading. This inherent reversible rotation originated from a back stress-driven dislocation slip process that was more active for larger grains. These results provide insights into the fundamental deformation mechanisms of nanograined metals and will help to guide strategies for material design and engineering applications.