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Recent years have seen a surge in service robots built on the ROS framework, where effective path planning algorithms are crucial for their successful operation. However, real-world operation presents challenges due to changes in environmental features and unexpected dynamic obstacles. If the path planning algorithms fail to update the state of the map layers in a timely manner, it can result in mission failures for the robots. Therefore, this study proposes a novel Motion Trajectory Analysis Regulator Navigation Framework within the ROS system. This framework incorporates path planning regulators for both global and local path planning algorithms, effectively mitigating path planning failures caused by dynamic environmental changes. For enhanced flexibility in path planning and dynamic obstacle avoidance, this framework proposes the ADRRT* algorithm for global path planning and the FGM-DWA algorithm for local path planning, replacing the traditional A* and DWA algorithms, respectively. Real-field experiments with a service robot demonstrate that the proposed methods not only ensure successful navigation with 100% success rate and a 23% improvement in time efficiency but also effectively handle dynamic and U-shaped obstacles, overcoming the challenge of path planning failures.

Abstract Background The PI3K/AKT pathway transduces the majority of the metabolic actions of insulin. In addition to cytosolic targets, insulin-stimulated phospho-AKT also translocates to mitochondria in the myocardium. Mouse models of diabetes exhibit impaired mitochondrial AKT signaling but the implications of this on cardiac structure and function is unknown. We hypothesized that loss of mitochondrial AKT signaling is a critical step in cardiomyopathy and reduces cardiac oxidative phosphorylation. Methods To focus our investigation on the pathophysiological consequences of this mitochondrial signaling pathway, we generated transgenic mouse models of cardiac-specific, mitochondria-targeting, dominant negative AKT1 (CAMDAKT) and constitutively active AKT1 expression (CAMCAKT). Myocardial structure and function were examined using echocardiography, histology, and biochemical assays. We further investigated the underlying effects of mitochondrial AKT1 on mitochondrial structure and function, its interaction with ATP synthase, and explored in vivo metabolism beyond the heart. Results Upon induction of dominant negative mitochondrial AKT1, CAMDAKT mice developed cardiac fibrosis accompanied by left ventricular hypertrophy and dysfunction. Cardiac mitochondrial oxidative phosphorylation efficiency and ATP content were reduced, mitochondrial cristae structure was lost, and ATP synthase structure was compromised. Conversely, CAMCAKT mice were protected against development of diabetic cardiomyopathy when challenged with a high calorie diet. Activation of mitochondrial AKT1 protected cardiac function and increased fatty acid uptake in myocardium. In addition, total energy expenditure was increased in CAMCAKT mice, accompanied by reduced adiposity and reduced development of fatty liver. Conclusion CAMDAKT mice modeled the effects of impaired mitochondrial signaling which occurs in the diabetic myocardium. Disruption of this pathway is a key step in the development of cardiomyopathy. Activation of mitochondrial AKT1 in CAMCAKT had a protective role against diabetic cardiomyopathy as well as improved metabolism beyond the heart.

Chromatin-associated RNAs (caRNAs) form a relatively poorly recognized layer of the epigenome. The caRNAs reported to date are transcribed from the nuclear genome. Here, leveraging a recently developed assay for detection of caRNAs and their genomic association, we report that mitochondrial RNAs (mtRNAs) are attached to the nuclear genome and constitute a subset of caRNA, thus termed mt-caRNA. In four human cell types analyzed, mt-caRNAs preferentially attach to promoter regions. In human endothelial cells (ECs), the level of mt-caRNA–promoter attachment changes in response to environmental stress that mimics diabetes. Suppression of a non-coding mt-caRNA in ECs attenuates stress-induced nascent RNA transcription from the nuclear genome, including that of critical genes regulating cell adhesion, and abolishes stress-induced monocyte adhesion, a hallmark of dysfunctional ECs. Finally, we report increased nuclear localization of multiple mtRNAs in the ECs of human diabetic donors, suggesting many mtRNA translocate to the nucleus in a cell stress and disease-dependent manner. These data nominate mt-caRNAs as messenger molecules responsible for mitochondrial–nuclear communication and connect the immediate product of mitochondrial transcription with the transcriptional regulation of the nuclear genome.

Summary: Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.

The migrating keratinocyte wound front is required for skin wound closure. Despite significant advances in wound healing research, we do not fully understand the molecular mechanisms that orchestrate collective keratinocyte migration. Here, we show that, in the wound front, the epidermal transcription factor Grainyhead like-3 (GRHL3) mediates decreased expression of the adherens junction protein E-cadherin; this results in relaxed adhesions between suprabasal keratinocytes, thus promoting collective cell migration and wound closure. Wound fronts from mice lacking GRHL3 in epithelial cells (Grhl3-cKO) have lower expression of Fascin-1 (FSCN1), a known negative regulator of E-cadherin. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on wounded keratinocytes shows decreased wound-induced chromatin accessibility near the Fscn1 gene in Grhl3-cKO mice, a region enriched for GRHL3 motifs. These data reveal a wound-induced GRHL3/FSCN1/E-cadherin pathway that regulates keratinocyte-keratinocyte adhesion during wound-front migration; this pathway is activated in acute human wounds and is altered in diabetic wounds in mice, suggesting translational relevance.

Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.

Abstract The signaling mechanisms controlling somatic cell reprogramming are not fully understood. In this study, we report a novel role for mitochondrial Akt1 signaling that enhanced somatic cell reprogramming efficiency. The role of mitochondrial Akt1 in somatic cell reprogramming was investigated by transducing fibroblasts with the four reprogramming factors (Oct4, Sox2, Klf4, c-Myc) in conjunction with Mito-Akt1, Mito-dnAkt1, or control virus. Mito-Akt1 enhanced reprogramming efficiency whereas Mito-dnAkt1 inhibited reprogramming. The resulting iPSCs formed embryoid bodies in vitro and teratomas in vivo. Moreover, Oct4 and Nanog promoter methylation was reduced in the iPSCs generated in the presence of Mito-Akt1. Akt1 was activated and translocated into mitochondria after growth factor stimulation in embryonic stem cells (ESCs). To study the effect of mitochondrial Akt in ESCs, a mitochondria-targeting constitutively active Akt1 (Mito-Akt1) was expressed in ESCs. Gene expression profiling showed upregulation of genes that promote stem cell proliferation and survival and down-regulation of genes that promote differentiation. Analysis of cellular respiration indicated similar metabolic profile in the resulting iPSCs and ESCs, suggesting comparable bioenergetics. These findings showed that activation of mitochondrial Akt1 signaling was required during somatic cell reprogramming.

Physical activity could be associated with psychosocial correlates of changes in eating behaviors required for weight loss. This field investigation assessed relationships of physical activity with early changes in psychosocial variables such as depression, fatigue, and body satisfaction; and their effect on fruit/vegetable and sweets intake and weight change. Emerging adult women from a university setting (Mage = 20.4 years, SD = 2.0; n = 36) and adult women from a community health-promotion setting (Mage = 45.6 years, SD = 7.3; n = 36), participating in the same cognitive-behavioral weight-loss program that initiated physical activity prior to nutrition changes, were first contrasted on measures of physical activity, psychosocial changes, eating changes, and weight; then on their theory-based interrelations. The emerging adult women had significantly higher baseline scores on depression and physical activity, and significantly lower scores on fruit/vegetable intake. Improvements over 3 months in the psychosocial and behavioral variables and weight were significant, but did not significantly differ by group. Weight loss means were -3.89 kg and -4.16 kg, respectively. Using aggregated data, serial mediation analyses identified a significant path from change in physical activity, to change in depression, to change in intake of sweets, to change in weight. Paths were also significant when improvement in tension and fatigue was entered as the psychosocial variable. Age group did not moderate those relationships. Findings improved understandings of age effects, and interrelations of psychosocial and behavioral predictors of short-term weight loss that could help longer-term treatment targets.

Los tratamientos conductuales para la diabetes a menudo han tenido éxito, y se pueden beneficiar de una mejor comprensión de los efectos relativos del tratamiento de dos focos comunes −pérdida de peso y aumento de actividad física− sobre la glucosa en sangre. Adultos con sobrepeso y obesos (N = 59; M = 60 años), con la hemoglobina A1c (HbA1c) y con diabetes, participaron durante 6 meses en un tratamiento conductual basado en principios de la teoría de la auto-eficacia y la teoría cognitiva social. El tratamiento se asoció con el aumento de actividad física de forma significativa, la reducción del índice de masa corporal (IMC), y la reducción de los niveles de HbA1c (ps < 0,001). Los cambios en el IMC y la actividad física presentaban una parte significativa de la varianza en el cambio en la HbA1c, R2 = 0,13, p = 0,023. El cambio en la cantidad de actividad física β = −0,36, p = 0,007, pero sin cambiar el IMC, β = −0,03, p = 0,792, contribuyó significativamente a la varianza en el cambio de HbA1c encontrado. No hubo un efecto según el sexo de los participantes. La discusión se centró en cómo los resultados podrían afectar la eficacia, la eficiencia y la aplicación de tratamientos conductuales para el tratamiento de la diabetes.

The fundamental repeating unit of eukaryotic chromatin is the nucleosome. Besides being involved in packaging DNA, nucleosome organization plays an important role in transcriptional regulation and cellular identity. Currently, there is much debate about the major determinants of the nucleosome architecture of a genome and its significance with little being known about its role in stem cells. To address these questions, we performed ultra-deep sequencing of nucleosomal DNA in two human embryonic stem cell lines and integrated our data with numerous epigenomic maps. Our analyses have revealed that the genome is a determinant of nucleosome organization with transcriptionally inactive regions characterized by a "ground state" of nucleosome profiles driven by underlying DNA sequences. DNA sequence preferences are associated with heterogeneous chromatin organization around transcription start sites. Transcription, histone modifications, and DNA methylation alter this "ground state" by having distinct effects on both nucleosome positioning and occupancy. As the transcriptional rate increases, nucleosomes become better positioned. Exons transcribed and included in the final spliced mRNA have distinct nucleosome profiles in comparison to exons not included at exon-exon junctions. Genes marked by the active modification H3K4m3 are characterized by lower nucleosome occupancy before the transcription start site compared to genes marked by the inactive modification H3K27m3, while bivalent domains, genes associated with both marks, lie exactly in the middle. Combinatorial patterns of epigenetic marks (chromatin states) are associated with unique nucleosome profiles. Nucleosome organization varies around transcription factor binding in enhancers versus promoters. DNA methylation is associated with increasing nucleosome occupancy and different types of methylations have distinct location preferences within the nucleosome core particle. Finally, computational analysis of nucleosome organization alone is sufficient to elucidate much of the circuitry of pluripotency. Our results, suggest that nucleosome organization is associated with numerous genomic and epigenomic processes and can be used to elucidate cellular identity.

Deciphering the multitude of epigenomic and genomic factors that influence the mutation rate is an area of great interest in modern biology. Recently, chromatin has been shown to play a part in this process. To elucidate this relationship further, we integrated our own ultra-deep sequenced human nucleosomal DNA data set with a host of published human genomic and cancer genomic data sets. Our results revealed, that differences in nucleosome occupancy are associated with changes in base-specific mutation rates. Increasing nucleosome occupancy is associated with an increasing transition to transversion ratio and an increased germline mutation rate within the human genome. Additionally, cancer single nucleotide variants and microindels are enriched within nucleosomes and both the coding and non-coding cancer mutation rate increases with increasing nucleosome occupancy. There is an enrichment of cancer indels at the theoretical start (74 bp) and end (115 bp) of linker DNA between two nucleosomes. We then hypothesized that increasing nucleosome occupancy decreases access to DNA by DNA repair machinery and could account for the increasing mutation rate. Such a relationship should not exist in DNA repair knockouts, and we thus repeated our analysis in DNA repair machinery knockouts to test our hypothesis. Indeed, our results revealed no correlation between increasing nucleosome occupancy and increasing mutation rate in DNA repair knockouts. Our findings emphasize the linkage of the genome and epigenome through the nucleosome whose properties can affect genome evolution and genetic aberrations such as cancer.

A late-stage photoisomerization/cyclization union tactic, in conjunction with Type I Anion Relay Chemistry (ARC), permits enantioselective total syntheses and then biological evaluation of (+)-peniciketals A and B. The photochemical protocol was further showcased by an efficient three-step construction of the architecturally complex polycyclic skeleton found in (-)-diocollettines A. The mechanism and diastereoselectivity of the photochemical protocol have also been explored by both experiment and density functional theory calculations.

The migrating keratinocyte wound front is required for skin wound closure. Despite significant advances in wound healing research, we do not fully understand the molecular mechanisms that orchestrate collective keratinocyte migration. Here, we show that, in the wound front, the epidermal transcription factor Grainyhead like-3 (GRHL3) mediates decreased expression of the adherens junction protein E-cadherin; this results in relaxed adhesions between suprabasal keratinocytes, thus promoting collective cell migration and wound closure. Wound fronts from mice lacking GRHL3 in epithelial cells (Grhl3-cKO) have lower expression of Fascin-1 (FSCN1), a known negative regulator of E-cadherin. Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on wounded keratinocytes shows decreased wound-induced chromatin accessibility near the Fscn1 gene in Grhl3-cKO mice, a region enriched for GRHL3 motifs. These data reveal a wound-induced GRHL3/FSCN1/E-cadherin pathway that regulates keratinocyte-keratinocyte adhesion during wound-front migration; this pathway is activated in acute human wounds and is altered in diabetic wounds in mice, suggesting translational relevance.

Mitochondrial biogenesis and function are controlled by anterograde regulatory pathways involving more than 1000 nuclear-encoded proteins. Transcriptional networks controlling the nuclear-encoded mitochondrial genes remain to be fully elucidated. Here, we show that histone demethylase LSD1 KO from adult mouse liver (LSD1-LKO) reduces the expression of one-third of all nuclear-encoded mitochondrial genes and decreases mitochondrial biogenesis and function. LSD1-modulated histone methylation epigenetically regulates nuclear-encoded mitochondrial genes. Furthermore, LSD1 regulates gene expression and protein methylation of nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), which controls the final step of NAD+ synthesis and limits NAD+ availability in the nucleus. Lsd1 KO reduces NAD+-dependent SIRT1 and SIRT7 deacetylase activity, leading to hyperacetylation and hypofunctioning of GABPβ and PGC-1α, the major transcriptional factor/cofactor for nuclear-encoded mitochondrial genes. Despite the reduced mitochondrial function in the liver, LSD1-LKO mice are protected from diet-induced hepatic steatosis and glucose intolerance, partially due to induction of hepatokine FGF21. Thus, LSD1 orchestrates a core regulatory network involving epigenetic modifications and NAD+ synthesis to control mitochondrial function and hepatokine production.

Kidney tubular dysfunction contributes to acute kidney injury and to the transition to chronic kidney disease. Although tubular mitochondria have been implicated in the pathophysiology of kidney failure, the mechanisms are not yet clear. Here, we demonstrated that ischemia-reperfusion injury induced acute translocation and activation of mitochondrial protein kinase B (also known as AKT1) in the kidney tubules. We hypothesized that mitochondrial AKT1 signaling protects against the development of acute kidney injury and subsequent chronic kidney disease. To test this prediction, we generated two novel kidney tubule-specific transgenic mouse strains with inducible expression of mitochondria-targeted dominant negative AKT1 or constitutively active AKT1, using a Cre-Lox strategy. Inhibition of mitochondrial AKT1 in mitochondria-targeted dominant negative AKT1 mice aggravated azotemia, tubular injuries, kidney fibrosis, glomerulosclerosis, and negatively impacted survival after ischemia-reperfusion injury. Conversely, enhancing tubular mitochondrial AKT1 signaling in mitochondria-targeted constitutively active AKT1 mice attenuated kidney injuries, protected kidney function, and significantly improved survival after ischemia-reperfusion injury (76.9% vs. 20.8%, respectively). Uncoupled mitochondrial respiration and increased oxidative stress was found in the kidney tubules when mitochondria AKT1 was inhibited, supporting the role of mitochondrial dysfunction in the pathophysiology of kidney failure. Thus, our studies suggest tubular mitochondrial AKT1 signaling could be a novel target to develop new strategies for better prevention and treatment of kidney injury.

Altered cellular metabolism is believed to be an important contributor to pathogenesis of the neurodegenerative disorder Huntington's disease (HD). Research has primarily focused on mitochondrial toxicity, which can cause death of the vulnerable striatal neurons, but other aspects of metabolism have also been implicated. Most previous studies have been carried out using postmortem human brain or non-human cells. Here, we studied bioenergetics in an induced pluripotent stem cell-based model of the disease. We found decreased adenosine triphosphate (ATP) levels in HD cells compared to controls across differentiation stages and protocols. Proteomics data and multiomics network analysis revealed normal or increased levels of mitochondrial messages and proteins, but lowered expression of glycolytic enzymes. Metabolic experiments showed decreased spare glycolytic capacity in HD neurons, while maximal and spare respiratory capacities driven by oxidative phosphorylation were largely unchanged. ATP levels in HD neurons could be rescued with addition of pyruvate or late glycolytic metabolites, but not earlier glycolytic metabolites, suggesting a role for glycolytic deficits as part of the metabolic disturbance in HD neurons. Pyruvate or other related metabolic supplements could have therapeutic benefit in HD.

Fully decarbonizing global industry is essential to achieving climate stabilization, and reaching net zero greenhouse gas emissions by 2050–2070 is necessary to limit global warming to 2 °C. This paper assembles and evaluates technical and policy interventions, both on the supply side and on the demand side. It identifies measures that, employed together, can achieve net zero industrial emissions in the required timeframe. Key supply-side technologies include energy efficiency (especially at the system level), carbon capture, electrification, and zero-carbon hydrogen as a heat source and chemical feedstock. There are also promising technologies specific to each of the three top-emitting industries: cement, iron & steel, and chemicals & plastics. These include cement admixtures and alternative chemistries, several technological routes for zero-carbon steelmaking, and novel chemical catalysts and separation technologies. Crucial demand-side approaches include material-efficient design, reductions in material waste, substituting low-carbon for high-carbon materials, and circular economy interventions (such as improving product longevity, reusability, ease of refurbishment, and recyclability). Strategic, well-designed policy can accelerate innovation and provide incentives for technology deployment. High-value policies include carbon pricing with border adjustments or other price signals; robust government support for research, development, and deployment; and energy efficiency or emissions standards. These core policies should be supported by labeling and government procurement of low-carbon products, data collection and disclosure requirements, and recycling incentives. In implementing these policies, care must be taken to ensure a just transition for displaced workers and affected communities. Similarly, decarbonization must complement the human and economic development of low- and middle-income countries.

The signaling mechanisms controlling somatic cell reprogramming are not fully understood. In this study, we report a novel role for mitochondrial Akt1 signaling that enhanced somatic cell reprogramming efficiency. The role of mitochondrial Akt1 in somatic cell reprogramming was investigated by transducing fibroblasts with the four reprogramming factors (Oct4, Sox2, Klf4, c-Myc) in conjunction with Mito-Akt1, Mito-dnAkt1, or control virus. Mito-Akt1 enhanced reprogramming efficiency whereas Mito-dnAkt1 inhibited reprogramming. The resulting iPSCs formed embryoid bodies in vitro and teratomas in vivo. Moreover, Oct4 and Nanog promoter methylation was reduced in the iPSCs generated in the presence of Mito-Akt1. Akt1 was activated and translocated into mitochondria after growth factor stimulation in embryonic stem cells (ESCs). To study the effect of mitochondrial Akt in ESCs, a mitochondria-targeting constitutively active Akt1 (Mito-Akt1) was expressed in ESCs. Gene expression profiling showed upregulation of genes that promote stem cell proliferation and survival and down-regulation of genes that promote differentiation. Analysis of cellular respiration indicated similar metabolic profile in the resulting iPSCs and ESCs, suggesting comparable bioenergetics. These findings showed that activation of mitochondrial Akt1 signaling was required during somatic cell reprogramming.

Phosphoglycerate kinase-1 (PGK1) deficiency is a rare X-linked disorder caused by pathogenic variants in the PGK1 gene. Complete loss-of-function variants have not been reported in this gene, indicating that residual enzyme function is critical for viability in males. Therefore, copy number variants (CNVs) that include single exon or multiple exon deletions or duplications are generally not expected in individuals with PGK1 deficiency. Here we describe a 64-year-old male presenting with a family history (three additional affected males) and a personal history of childhood-onset metabolic myopathy that involves episodes of muscle pain, stiffness after activity, exercise intolerance, and myoglobinuria after exertion. Biochemical analysis on a muscle biopsy indicated significantly reduced activity (15% compared to normal) for phosphoglycerate kinase (PGK1), a glycolytic enzyme encoded by PGK1. A diagnosis of PGK1 deficiency was established by molecular analysis which detected an approximately 886 kb deletion involving the polyadenylation site in the 3'UTR of the PGK1 gene. RNA analysis showed significantly reduced PGK1 transcript levels (30% compared to normal). This is the first deletion reported in the PGK1 gene and is the first pathogenic variant involving the 3'UTR polyadenylation site of this gene. Our report emphasizes the role of 3'UTR variants in human disorders and underscores the need for exploring noncoding regions of disease-associated genes when seeking a molecular diagnosis.

Intra-tumoral heterogeneity is associated with therapeutic resistance of cancer and there exists a need to non-invasively identify functional tumor subpopulations responsible for tumor recurrence. Reduced nicotinamide adenine dinucleotide (NADH) is a metabolic coenzyme essential in cellular respiration. Fluorescence lifetime imaging microscopy (FLIM) of NADH has been demonstrated to be a powerful label-free indicator for inferring metabolic states of living cells. Using FLIM, we identified a significant shift towards longer NADH fluorescence lifetimes, suggesting an increase in the fraction of protein-bound NADH, in the invasive stem-like tumor-initiating cell (STIC) subpopulation relative to the tumor mass-forming cell (TMC) subpopulation of malignant gliomas. By applying our previously studied model to transition glioma from a majority of STIC to a majority of TMC in serum-adherent culture conditions following serial passages, we compared changes in NADH states, cellular respirations (oxidative phosphorylation and glycolysis), EGFR expression, and cell-growth speed over passages. We identified a significant positive correlation between free-NADH fraction and cell growth, which was related to an increase of TMC fraction. In comparison, the increase of EGFR and cellular respirations preceded all these changes. In conclusion, FLIM of NADH provides a non-invasive method to monitor the dynamics of tumor heterogeneity before and after treatment.

ObjectiveThe prevalence of diabetes mellitus (DM) is increasing rapidly, particularly in Asia. Asian immigrants in Western countries are a fast-growing population who carry both intrinsic risks due to their genetic background and extrinsic risks associated with Western lifestyles. However, recent trends in diabetes prevalence and associated risk factors among Asian immigrants in the USA are not well understood.Research design and methodsWe examined adults aged 18 and older from the recent California Health Interview Survey data sets from 2003 to 2013 to determine prevalence of known DM among first-generation Asian immigrants and whites. The impact of various DM risk factors in Asian immigrants relative to whites was analyzed and multivariable regression models were constructed to obtain adjusted DM risk in Asian immigrants versus in whites.ResultsAcross the study span, we identified 2007 first-generation Asian immigrants and 14 668 whites as having known DM or prediabetes mellitus (pre-DM). From 2003 to 2013, the prevalence of DM and pre-DM combined rose from 6.8% to 12.4% in Asian immigrants and 5.5% to 6.9% in whites. Much of the increase could be attributed to pre-DM, which rose from 0.7% to 3.2% in Asian immigrants during the study period. The impacts of age and body mass index on DM risk were consistently greater in Asian immigrants than in whites. Non-DM Asian immigrants were found less likely to engage in physical activity than were non-DM whites. After adjustment of various associated factors, Asian immigrants were more likely than whites to have DM and this relative risk for DM gradually increased across the study period.ConclusionsA rising prevalence of known DM and particularly pre-DM among Asian immigrants in California was observed during the previous decade. To reduce the burden of diabetes and its complications, future strategies should consider specific risk factors for this ethnic group, including encouraging physical activity.

ObjectiveThe aim of this study was to identify liver proteome changes in a mouse model of severe insulin resistance and markedly decreased leptin levels.MethodsTwo-dimensional differential gel electrophoresis was utilized to identify liver proteome changes in AKT1(+/-)/AKT2(-/-) mice. Proteins with altered levels were identified with tandem mass spectrometry. Ingenuity Pathway Analysis was performed for the interpretation of the biological significance of the observed proteomic changes.Results11 proteins were identified from 2 biological replicates to be differentially expressed by a ratio of at least 1.3 between age-matched insulin resistant (Akt1(+/-)/Akt2(-/-)) and wild type mice. Albumin and mitochondrial ornithine aminotransferase were detected from multiple spots, which suggest post-translational modifications. Enzymes of the urea cycle were common members of top regulated pathways.ConclusionOur results help to unveil the regulation of the liver proteome underlying altered metabolism in an animal model of severe insulin resistance.

This study examined the priority health behaviors among Chinese youth by administering a questionnaire to 1,917 undergraduates enrolled in three universities in China. The response rate was 89.7%. This survey found that 75.2% of the participants tried cigarettes at least once during their lifetime, over half had their first cigarette and alcoholic drink before age 15, and over 80% had their first cigarette and alcoholic drink by age 18. During the month preceding the survey, 50.6% consumed five or more alcoholic drinks on a single occasion and 8.1% carried a weapon at least once. Twenty-two percent had at least three servings of fruits and vegetables the day before the survey, 35.3% engaged in vigorous physical activity on three or more of the seven days preceding the survey, 66.9% rarely or never wore motorcycle helmets, 13.4% seriously considered attempting suicide, and 3.9% had an STI. Results were analyzed by sex, age, and hometown. Results show that many Chinese college students have engaged in behaviors that put their health in danger. Effective health education programs are needed to reduce health risks leading to deaths and disabilities among Chinese youth. (Contains 10 tables.) [Abstract provided in English, Spanish, and Chinese.]

The phenotypic and genetic diversity that define tumor subpopulations within high-grade glioma can lead to therapeutic resistance and tumor recurrence. Given that cranial irradiation is a frontline treatment for malignant glioma, understanding how irradiation selectively effects different cellular subpopulations within these heterogeneous cancers should help identify interventions targeted to better combat this deadly disease. To analyze the radiation response of distinct glioma subpopulations, 2 glioma cells lines (U251, A172) were cultured under conditions that promoted either adherence or non-adherent spheroids. Past work has demonstrated that subpopulations derived from defined culture conditions exhibit differences in karyotype, proliferation, gene expression and tumorigenicity. Spheroid cultures from each of the glioma cell lines were found to be more radiosensitive, which was consistent with higher levels of oxidative stress and lower levels of both oxidative phosphorylation and glycolytic metabolism 1 week following irradiation. In contrast, radioresistant non-spheroid parental cultures showed increased glycolytic activity in response to irradiation, while oxidative phosphorylation was affected to a lesser extent. Overall these data suggest that prolonged radiation-induced oxidative stress can compromise the metabolic state of certain glioma subpopulations thereby altering their sensitivity to an important therapeutic intervention used routinely for the control of glioma.

Advanced chronic kidney disease (CKD) is associated with impaired exercise capacity, skeletal muscle dysfunction, and oxidative stress. Mitochondria are the primary source for energy production and generation of reactive oxygen species (ROS). Mitochondrial state 3 respiration, mitochondrial complex I enzyme activity, and tissue porin/actin ratio were determined in the gastrocnemius muscle of male SD rats 14 weeks after 5/6 nephrectomy (CKD) or sham-operation (control). The CKD group exhibited azotemia, hypertension, significant reduction (-39%) of state 3 mitochondrial respiration, and a significant increase in the mitochondrial complex I enzyme activity. The latter is the first step in oxidative phosphorylation, a process linked to production of ROS. These abnormalities were associated with a significant reduction in muscle porin/β actin ratio denoting substantial reduction of mitochondrial mass in skeletal muscle of animals with CKD. CKD results in impaired mitochondrial respiration, reduced muscle mitochondrial mass, depressed energy production and increased ROS generation in the skeletal muscle. These events can simultaneously contribute to the reduction of exercise capacity and oxidative stress in CKD.

Background: Previous studies suggested that mitochondrial antibodies contribute to pemphigus vulgaris (PV).Results: PV sera elicited mitochondrial damage, and mitochondria-protecting drugs exhibited protective effect in cell culture and mouse skin.Conclusion: PV antibodies altered O2 respiration, disrupted electron transfer chain, and increased reactive oxygen species.Significance: Results provide the mechanism of therapeutic action and justify the use of mitochondria-protecting drugs in PV.The development of nonhormonal treatment of pemphigus vulgaris (PV) has been hampered by a lack of clear understanding of the mechanisms leading to keratinocyte (KC) detachment and death in pemphigus. In this study, we sought to identify changes in the vital mitochondrial functions in KCs treated with the sera from PV patients and healthy donors. PV sera significantly increased proton leakage from KCs, suggesting that PV IgGs increase production of reactive oxygen species. Indeed, measurement of intracellular reactive oxygen species production showed a drastic increase of cell staining in response to treatment by PV sera, which was confirmed by FACS analysis. Exposure of KCs to PV sera also caused dramatic changes in the mitochondrial membrane potential detected with the JC-1 dye. These changes can trigger the mitochondria-mediated intrinsic apoptosis. Although sera from different PV patients elicited unique patterns of mitochondrial damage, the mitochondria-protecting drugs nicotinamide (also called niacinamide), minocycline, and cyclosporine A exhibited a uniform protective effect. Their therapeutic activity was validated in the passive transfer model of PV in neonatal BALB/c mice. The highest efficacy of mitochondrial protection of the combination of these drugs found in mitochondrial assay was consistent with the ability of the same drug combination to abolish acantholysis in mouse skin. These findings provide a theoretical background for clinical reports of the efficacy of mitochondria-protecting drugs in PV patients. Pharmacological protection of mitochondria and/or compensation of an altered mitochondrial function may therefore become a novel approach to development of personalized nonhormonal therapies of patients with this potentially lethal autoimmune blistering disease.

The distinction between mild pathogenic mtDNA mutations and population polymorphisms can be ambiguous because both are homoplasmic, alter conserved functions, and correlate with disease. One possible explanation for this ambiguity is that the same variant may have different consequences in different contexts. The NADH dehydrogenase subunit 1 (ND1) nucleotide 3394 T > C (Y30H) variant is such a case. This variant has been associated with Leber hereditary optic neuropathy and it reduces complex I activity and cellular respiration between 7% and 28% on the Asian B4c and F1 haplogroup backgrounds. However, complex I activity between B4c and F1 mtDNAs, which harbor the common 3394T allele, can also differ by 30%. In Asia, the 3394C variant is most commonly associated with the M9 haplogroup, which is rare at low elevations but increases in frequency with elevation to an average of 25% of the Tibetan mtDNAs (odds ratio = 23.7). In high-altitude Tibetan and Indian populations, the 3394C variant occurs on five different macrohaplogroup M haplogroup backgrounds and is enriched on the M9 background in Tibet and the C4a4 background on the Indian Deccan Plateau (odds ratio = 21.9). When present on the M9 background, the 3394C variant is associated with a complex I activity that is equal to or higher than that of the 3394T variant on the B4c and F1 backgrounds. Hence, the 3394C variant can either be deleterious or beneficial depending on its haplogroup and environmental context. Thus, this mtDNA variant fulfills the criteria for a common variant that predisposes to a “complex” disease.

Background: Young adults gain weight faster and suffer from chronic diseases at a younger age than their older counterparts. Existing behavioral obesity treatments included few young adults, and their effects on young adults remain unknown. Purpose: The purpose of this study was to explore whether a behavioral treatment that was effective in weight loss for mostly middle-aged women would be effective for young women. Methods: One hundred eleven female undergraduates with obesity recruited from a large public university in the Southeastern United States in 2014-2016 received treatment, including 6 individual exercise support sessions over 6 months and 20 biweekly group nutrition sessions. Measurements include weight, waist circumference, physical activity, diet, mood, and exercise- and eating-related self-regulation and self-efficacy at baseline and at months 3 and 6. Results: Attrition was 65.8% at month 3 and 87.4% at month 6. Paired t tests show significant reductions in weight and significant improvements in weight loss-related behaviors and psychological variables at month 3. More average weight was lost at month 6. Discussion: Despite high attrition, the treatment demonstrated some positive effects for the young college women who continued attending sessions. Translation to Health Education Practice: Health Educators should explore reasons for attrition among college students with obesity and develop treatment components to help them lose excess weight.

Autoreactive memory T lymphocytes are implicated in the pathogenesis of autoimmune diseases. Here we demonstrate that disease-associated autoreactive T cells from patients with type-1 diabetes mellitus or rheumatoid arthritis (RA) are mainly CD4+ CCR7- CD45RA- effector memory T cells (T(EM) cells) with elevated Kv1.3 potassium channel expression. In contrast, T cells with other antigen specificities from these patients, or autoreactive T cells from healthy individuals and disease controls, express low levels of Kv1.3 and are predominantly naïve or central-memory (T(CM)) cells. In T(EM) cells, Kv1.3 traffics to the immunological synapse during antigen presentation where it colocalizes with Kvbeta2, SAP97, ZIP, p56(lck), and CD4. Although Kv1.3 inhibitors [ShK(L5)-amide (SL5) and PAP1] do not prevent immunological synapse formation, they suppress Ca2+-signaling, cytokine production, and proliferation of autoantigen-specific T(EM) cells at pharmacologically relevant concentrations while sparing other classes of T cells. Kv1.3 inhibitors ameliorate pristane-induced arthritis in rats and reduce the incidence of experimental autoimmune diabetes in diabetes-prone (DP-BB/W) rats. Repeated dosing with Kv1.3 inhibitors in rats has not revealed systemic toxicity. Further development of Kv1.3 blockers for autoimmune disease therapy is warranted.

Oleylethanolamide (OEA) is a natural fatty acid ethanolamide produced in the heart, but its biological actions in myocardium have not yet been defined. This study was carried out to determine whether OEA could be used to prevent the development of heart failure or improve evolving heart failure. We studied in vivo and in vitro actions of OEA in cardiac muscle. In an animal model of doxorubicin cardiomyopathy, OEA showed robust effects and attenuated the progression of systolic/diastolic dysfunction and ventricular remodeling. During evolving doxorubicin cardiomyopathy, a therapeutic course of OEA treatment partially restored myocardial function. The preventive and therapeutic effects of OEA were associated with significant improvement of survival. To investigate the mechanism of OEA action in cardiac muscle, we have carried out in vitro experiments in cultured cardiomyocytes. The results showed that OEA, through activation of Ras-Raf-1-Mek-Erk signaling, inhibited doxorubicin-induced apoptosis. Additional experiments showed that OEA activation of the Erk pathway involved activation of Neu/ErbB2 receptor, which suggests OEA actions in cardiac muscle might require activation of Neu/ErbB2. In summary, OEA improved ventricular remodeling and augmented cardiac function in doxorubicin cardiomyopathy, possibly involving activation of Neu/ErbB2 and Ras-Erk signaling. These findings suggest OEA is a novel cardioprotective compound that may be used to develop new strategies for the management of cardiomyopathy.

Propagating changes from one place in a product line architecture to another is a difficult problem that occurs in a variety of settings. Currently, no automated tools exist that help an architect in doing so, and performing the task by hand in the face of a large product line architecture can be error-prone and difficult. To address this problem, we have built a set of tools for automating the process. Our approach breaks down into a two-step solution: (1) automatically determining the difference between two selected (versions of) a product architecture, and (2) automatically merging the difference back into a different location in the original product line architecture. In this paper, we detail each of these two steps and evaluate our solution on an example word processor product line architecture.