FGF21 is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. The mechanism of FGF21 action and the tissues responsible for these effects have been controversial, with both ...adipose tissues and the central nervous system having been identified as the target site mediating FGF21-dependent increases in insulin sensitivity, energy expenditure, and weight loss. Here we show that, while FGF21 signaling to adipose tissue is required for the acute insulin-sensitizing effects of FGF21, FGF21 signaling to adipose tissue is not required for its chronic effects to increase energy expenditure and lower body weight. Also, in contrast to previous studies, we found that adiponectin is dispensable for the metabolic effects of FGF21 in increasing insulin sensitivity and energy expenditure. Instead, FGF21 acutely enhances insulin sensitivity through actions on brown adipose tissue. Our data reveal that the acute and chronic effects of FGF21 can be dissociated through adipose-dependent and -independent mechanisms.
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•FGF21 signaling to adipose tissues is required for acute insulin sensitization•Adiponectin is dispensable for the metabolic effects of FGF21•FGF21 reduces body weight by signaling to nonadipose tissues•FGF21 signals to brown adipocytes to mediate its acute glucose-lowering effects
Pharmacological administration of FGF21 increases insulin sensitivity and promotes weight loss. BonDurant et al. show that FGF21 signaling to adipose tissues is essential for the acute insulin-sensitizing effects of FGF21, but not for its effects on body weight. Importantly, loss of FGF21 signaling specifically to brown adipocytes disrupts FGF21-mediated glucose disposal.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Processing raw genomic data for downstream applications such as imputation, association studies, and modeling requires numerous third-party bioinformatics software tools. It is highly time-consuming ...and resource-intensive with computational demands and storage limitations that pose significant challenges that increase cost. The use of software tools independent of one another, in a disjointed stepwise fashion, increases the difficulty and sets forth higher error rates because of fragmented job executions in alignment, variant calling, and/or build conversion complications. As sequencing data availability grows, the ability for biologists to process it using stable, automated, and reproducible workflows is paramount as it significantly reduces the time to generate clean and reliable data. The Iliad suite of genomic data workflows was developed to provide users with seamless file transitions from raw genomic data to a quality-controlled variant call format (VCF) file for downstream applications. Iliad benefits from the efficiency of the Snakemake best practices framework coupled with Singularity and Docker containers for repeatability, portability, and ease of installation. This feat is accomplished from the onset with download acquisitions of any raw data type (FASTQ, CRAM, IDAT) straight through to the generation of a clean merged data file that can combine any user-preferred datasets using robust programs such as BWA, Samtools, and BCFtools. Users can customize and direct their workflow with one straightforward configuration file. Iliad is compatible with Linux, MacOS, and Windows platforms and scalable from a local machine to a high-performance computing cluster. Iliad offers automated workflows with optimized time and resource management that are comparable to other workflows available but generates analysis-ready VCF files from the most common datatypes using a single command. The storage footprint challenge of genomic data is overcome by utilizing temporary intermediate files before the final VCF is generated. This file is ready for use in imputation, genome-wide association study (GWAS) pipelines, high-throughput population genetics studies, select gene candidate studies, and more. Iliad was developed to be portable, compatible, scalable, robust, and repeatable with a simplistic setup, so biologists that are less familiar with programming can manage their own big data with this open-source suite of workflows.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Over 4 decades, short- and long-term survival for children with congenital heart disease (CHD) has significantly increased. Those with complex CHD have a 1-year mortality rate of approximately 25%. ...Prenatal access to palliative care ensures a comprehensive approach to the infant's physical, emotional, spiritual, and psychosocial well-being and offers enhanced support for parents and families while providing an interprofessional approach to care. Pediatric cardiac provider attitudes, knowledge, patterns of prenatal palliative care, and consultation for fetuses with complex heart disease to guide increased and appropriate prenatal consultation were explored for a quality improvement project completed at a single institution. A retrospective cardiac database review identified that 21.5% of maternal patients seen prenatally and carrying a fetus with complex CHD would have qualified for prenatal palliative care consultation. To increase prenatal palliative care consultation, a pathway for referral was developed. A pre-evaluation of pediatric cardiac provider attitudes regarding palliative care was measured. Survey data informed the intervention phase of prenatal palliative care educational material development, which was presented to pediatric cardiac providers. The number of prenatal palliative care consults was tracked. A postintervention survey completed by pediatric cardiac providers showed increased understanding and utilization of palliative care for comfort and support and not just reserved for death preparation. Greater than 93% agreed or strongly agreed that they gained a better understanding of appropriate use of palliative/supportive care. As pediatric cardiac providers become more knowledgeable about early integration of palliative care, parents and infants will benefit greatly from referrals and initiation of palliative care at the time of prenatal diagnosis.
Exercise remains the most effective way to promote physical and metabolic wellbeing, but molecular mechanisms underlying exercise tolerance and its plasticity are only partially understood. In this ...study we identify musclin—a peptide with high homology to natriuretic peptides (NP)—as an exercise-responsive myokine that acts to enhance exercise capacity in mice. We use human primary myoblast culture and in vivo murine models to establish that the activity-related production of musclin is driven by Ca2+-dependent activation of Akt1 and the release of musclin-encoding gene (Ostn) transcription from forkhead box O1 transcription factor inhibition. Disruption ofOstnand elimination of musclin secretion in mice results in reduced exercise tolerance that can be rescued by treatment with recombinant musclin. Reduced exercise capacity in mice with disrupted musclin signaling is associated with a trend toward lower levels of plasma atrial NP (ANP) and significantly smaller levels of cyclic guanosine monophosphate (cGMP) and peroxisome proliferator-activated receptor gamma coactivator 1-α in skeletal muscles after exposure to exercise. Furthermore, in agreement with the established musclin ability to interact with NP clearance receptors, but not with NP guanyl cyclase-coupled signaling receptors, we demonstrate that musclin enhances cGMP production in cultured myoblasts only when applied together with ANP. Elimination of the activity-related musclin-dependent boost of ANP/cGMP signaling results in significantly lower maximum aerobic capacity, mitochondrial protein content, respiratory complex protein expression, and succinate dehydrogenase activity in skeletal muscles. Together, these data indicate that musclin enhances physical endurance by promoting mitochondrial biogenesis.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Automatic dense 3D surface registration is a powerful technique for comprehensive 3D shape analysis that has found a successful application in human craniofacial morphology research, particularly ...within the mandibular and cranial vault regions. However, a notable gap exists when exploring the frontal aspect of the human skull, largely due to the intricate and unique nature of its cranial anatomy. To better examine this region, this study introduces a simplified single-surface craniofacial bone mask comprising of 6707 quasi-landmarks, which can aid in the classification and quantification of variation over human facial bone surfaces. Automatic craniofacial bone phenotyping was conducted on a dataset of 31 skull scans obtained through cone-beam computed tomography (CBCT) imaging. The MeshMonk framework facilitated the non-rigid alignment of the constructed craniofacial bone mask with each individual target mesh. To gauge the accuracy and reliability of this automated process, 20 anatomical facial landmarks were manually placed three times by three independent observers on the same set of images. Intra- and inter-observer error assessments were performed using root mean square (RMS) distances, revealing consistently low scores. Subsequently, the corresponding automatic landmarks were computed and juxtaposed with the manually placed landmarks. The average Euclidean distance between these two landmark sets was 1.5 mm, while centroid sizes exhibited noteworthy similarity. Intraclass coefficients (ICC) demonstrated a high level of concordance (> 0.988), with automatic landmarking showing significantly lower errors and variation. These results underscore the utility of this newly developed single-surface craniofacial bone mask, in conjunction with the MeshMonk framework, as a highly accurate and reliable method for automated phenotyping of the facial region of human skulls from CBCT and CT imagery. This craniofacial template bone mask expansion of the MeshMonk toolbox not only enhances our capacity to study craniofacial bone variation but also holds significant potential for shedding light on the genetic, developmental, and evolutionary underpinnings of the overall human craniofacial structure.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Evidence from model organisms and clinical genetics suggests coordination between the developing brain and face, but the role of this link in common genetic variation remains unknown. We performed a ...multivariate genome-wide association study of cortical surface morphology in 19,644 individuals of European ancestry, identifying 472 genomic loci influencing brain shape, of which 76 are also linked to face shape. Shared loci include transcription factors involved in craniofacial development, as well as members of signaling pathways implicated in brain-face cross-talk. Brain shape heritability is equivalently enriched near regulatory regions active in either forebrain organoids or facial progenitors. However, we do not detect significant overlap between shared brain-face genome-wide association study signals and variants affecting behavioral-cognitive traits. These results suggest that early in embryogenesis, the face and brain mutually shape each other through both structural effects and paracrine signaling, but this interplay may not impact later brain development associated with cognitive function.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Melanocortin 4 receptor (MC4R) signaling mediates diverse physiological functions, including energy balance, glucose homeostasis, and autonomic activity. Although the lateral hypothalamic area (LHA) ...is known to express MC4Rs and to receive input from leptin-responsive arcuate proopiomelanocortin neurons, the physiological functions of MC4Rs in the LHA are incompletely understood. We report that MC4R(LHA) signaling regulates glucose tolerance and sympathetic nerve activity. Restoring expression of MC4Rs specifically in the LHA improves glucose intolerance in obese MC4R-null mice without affecting body weight or circulating insulin levels. Fluorodeoxyglucose-mediated tracing of whole-body glucose uptake identifies the interscapular brown adipose tissue (iBAT) as a primary source where glucose uptake is increased in MC4R(LHA) mice. Direct multifiber sympathetic nerve recording further reveals that sympathetic traffic to iBAT is significantly increased in MC4R(LHA) mice, which accompanies a significant elevation of Glut4 expression in iBAT. Finally, bilateral iBAT denervation prevents the glucoregulatory effect of MC4R(LHA) signaling. These results identify a novel role for MC4R(LHA) signaling in the control of sympathetic nerve activity and glucose tolerance independent of energy balance.
Health literacy is a nationwide public health concern. Low health literacy in adolescents is related to increased adolescent high-risk behaviors, which can negatively affect their overall health.
A ...quality improvement health literacy project was developed, implemented, and evaluated in a juvenile temporary detention center. Stakeholders identified pertinent health-related topics for discussion, including female body anatomy, sexual health, consent, pornography, sex trafficking, smoking, and anger management. Toolkits and pretest/posttest questionnaires guided weekly group sessions. Youth engaged in content during each session.
Group health literacy scores were examined to evaluate the program. Group comments were debriefed by facilitators after each session; 119 youth residents participated. Positive increases in health literacy and health knowledge were observed in all sessions for all groups.
Interactive health education programs for incarcerated youth can improve their health literacy and health knowledge and begin a path to decrease health inequities in this vulnerable population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Aberrant redox signaling underlies the pathophysiology of many chronic metabolic diseases, including type 2 diabetes (T2D). Methodologies aimed at rebalancing systemic redox homeostasis have had ...limited success. A noninvasive, sustained approach would enable the long-term control of redox signaling for the treatment of T2D. We report that static magnetic and electric fields (sBE) noninvasively modulate the systemic GSH-to-GSSG redox couple to promote a healthier systemic redox environment that is reducing. Strikingly, when applied to mouse models of T2D, sBE rapidly ameliorates insulin resistance and glucose intolerance in as few as 3 days with no observed adverse effects. Scavenging paramagnetic byproducts of oxygen metabolism with SOD2 in hepatic mitochondria fully abolishes these insulin sensitizing effects, demonstrating that mitochondrial superoxide mediates induction of these therapeutic changes. Our findings introduce a remarkable redox-modulating phenomenon that exploits endogenous electromagneto-receptive mechanisms for the noninvasive treatment of T2D, and potentially other redox-related diseases.
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•Combined static magnetic and electric fields (sBE) enhance insulin sensitivity•sBE is not associated with adverse effects•sBE triggers a systemic redox response to modulate insulin sensitivity•Scavenging mitochondrial superoxide in the liver abolishes the effects of sBE
Abnormal redox homeostasis contributes to the pathogenesis of type 2 diabetes. However, targeting redox systems remains a challenge. In this issue, Carter, Huang et al. demonstrate that static magnetic and electric fields can be used to modulate redox systems for the noninvasive treatment of type 2 diabetes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Objectives
We previously developed a real‐time fluorescence imaging topography scanning (RFITS) system for intraoperative multimodal imaging, image‐guided surgery, and dynamic surgical ...navigation. The RFITS can capture intraoperative fluorescence, color reflectance, and surface topography concurrently and offers accurate registration of multimodal images. The RFITS prototype is a promising system for multimodal image guidance and intuitive 3D visualization. In the current study, we investigated the capability of the RFITS system in intraoperative fluorescence vascular angiography for real‐time assessment of tissue perfusion.
Study Design/Materials and Methods
We conducted ex vivo imaging of fluorescence perfusion in a soft casting life‐sized human brain phantom. Indocyanine green (ICG) solutions diluted in dimethyl sulfoxide (DMSO) and human serum were injected into the brain phantom through the vessel simulating tube (2 ± 0.2 mm inner diameter) by an adjustable flow peristaltic pump. To demonstrate the translational potential of the system, an ICG/DMSO solution was perfused into blood vessels of freshly harvested porcine ears (n = 9, inner diameter from 0.56 to 1.27 mm). We subsequently performed in vivo imaging of fluorescence‐perfused vascular structures in rodent models (n = 10). 5 mg/ml ICG solutions prepared in sterile water were injected via the lateral tail vein. All targets were imaged by the RFITS prototype at a working distance of 350−400 mm.
Results
3D visualization of 10 µg/ml ICG‐labeled continuous moving serum in the brain phantom was obtained at an average signal‐to‐background ratio (SBR) of 1.74 ± 0.03. The system was able to detect intravenously diffused fluorescence in porcine tissues with an average SBR of 2.23 ± 0.22. The RFITS prototype provided real‐time monitoring of tissue perfusion in rats after intravenous (IV) administration of ICG. The maximum fluorescence intensity (average SBR = 1.94 ± 0.16, p < 0.001) was observed at Tpeak of ~30 seconds after the ICG signal was first detected (average SBR = 1.19 ± 0.13, p < 0.01).
Conclusions
We have conducted preclinical studies to demonstrate the feasibility of applying the RFITS system in real‐time fluorescence angiography and tissue perfusion assessment. Our system provides fluorescence/color composite images for intuitive visualization of tissue perfusion with 3D perception. The findings pave the way for future clinical translation.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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