Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat ...and are considered "metabolically healthy." However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease.
Oligonucleotides (ONs) can interfere with biomolecules representing the entire extended central dogma. Antisense gapmer, steric block, splice-switching ONs, and short interfering RNA drugs have been ...successfully developed. Moreover, antagomirs (antimicroRNAs), microRNA mimics, aptamers, DNA decoys, DNAzymes, synthetic guide strands for CRISPR Cas, and innate immunity-stimulating ONs are all in clinical trials. DNA-targeting, triplex-forming ONs and strand-invading ONs have made their mark on drug development research, but not yet as medicines. Both design and synthetic nucleic acid chemistry are crucial for achieving biologically active ONs. The dominating modifications are phosphorothioate linkages, base methylation, and numerous 2′-substitutions in the furanose ring, such as 2′-fluoro,
O
-methyl, or methoxyethyl. Locked nucleic acid and constrained ethyl, a related variant, are bridged forms where the 2′-oxygen connects to the 4′-carbon in the sugar. Phosphorodiamidate morpholino oligomers, carrying a modified heterocyclic backbone ring, have also been commercialized. Delivery remains a major obstacle, but systemic administration and intrathecal infusion are used for treatment of the liver and brain, respectively.
Huntington disease (HD) is an inherited neurodegenerative disorder caused by an expansion of the CAG repeat region in the first exon of the huntingtin gene. Neurodegeneration, which begins in the ...striatum and then spreads to other brain areas, is preceded by dysfunction in multiple aspects of neurotransmission across a variety of brain areas. This review will provide an overview of the neurochemical mediators and modulators of synaptic transmission that are disrupted in HD. This includes classical neurotransmitters like glutamate and gamma‐aminobutyric acid, modulators such as dopamine, adenosine and endocannabinoids, and molecules like brain‐derived neurotrophic factor which affect neurotransmission in a more indirect manner. Alterations in the functioning of these signaling pathways can occur across multiple brain regions such as striatum, cortex and hippocampus, and affect transmission and plasticity at the synapses within these regions, which may ultimately change behaviour and contribute to the pathophysiology of HD. The current state of knowledge in this area has already yielded useful information about the causes of synaptic dysfunction and selective cell death. A full understanding of the mechanisms and consequences of disruptions in synaptic function and plasticity will lend insight into the development of the symptoms of HD, and potential drug targets for ameliorating them.
Early Huntington disease is characterized by involuntary motor symptoms, especially chorea, due to dominance of direct pathway Striatal Projection Neurons (SPN) which facilitate movement. Initially, deficits in endocannabinoid and BDNF signaling, increased dopamine and GABA contribute to impair some forms of synaptic plasticity in indirect pathway SPNs, as well as their vulnerability to degeneration before other cell types. In this paper we summarize mutant huntington (mHtt)‐induced changes in neurotransmission in the striatum and cortex. DA, dopamine; dSPN, direct pathway SPN; eCB, endocannabinoid; iSPN, indirect pathway SPN.
Background: Age-associated declines in muscle mass and function are major risk factors for an impaired ability to carry out activities of daily living, falls, prolonged recovery time after ...hospitalization, and mortality in older adults. New strategies that can slow the age-related loss of muscle mass and function are needed to help older adults maintain adequate performance status to reduce these risks and maintain independence. Objective: We evaluated the efficacy of fish oil–derived n–3 (ω -3) PUFA therapy to slow the age-associated loss of muscle mass and function. Design: Sixty healthy 60–85-y-old men and women were randomly assigned to receive n–3 PUFA (n = 40) or corn oil (n = 20) therapy for 6 mo. Thigh muscle volume, handgrip strength, one-repetition maximum (1-RM) lower- and upper-body strength, and average power during isokinetic leg exercises were evaluated before and after treatment. Results: Forty-four subjects completed the study 29 subjects (73%) in the n–3 PUFA group; 15 subjects (75%) in the control group. Compared with the control group, 6 mo of n–3 PUFA therapy increased thigh muscle volume (3.6%; 95% CI: 0.2%, 7.0%), handgrip strength (2.3 kg; 95% CI: 0.8, 3.7 kg), and 1-RM muscle strength (4.0%; 95% CI: 0.8%, 7.3%) (all P < 0.05) and tended to increase average isokinetic power (5.6%; 95% CI: −0.6%, 11.7%; P = 0.075). Conclusion: Fish oil–derived n–3 PUFA therapy slows the normal decline in muscle mass and function in older adults and should be considered a therapeutic approach for preventing sarcopenia and maintaining physical independence in older adults. This study was registered at clinicaltrials.gov as NCT01308957.
Although live cell imaging is desirable, it is not always feasible and in many situations cells are fixed in order to provide a ‘snapshot’ of the nature and distribution of molecules within a cell ...while minimising changes from cell movement, sample degradation etc. There is a wide range of fixation methods available that act via different mechanisms, and on different cell components. Each method has advantages and disadvantages and a choice of what fixation method to choose for a particular experiment needs to take these factors into consideration. Here we used Raman spectroscopic imaging of live cells, and compared with cells preserved with aldehyde, or organic solvent-based fixation methods to assess the chemical changes induced by each fixative, and their impact on the quality of images that can be obtained from fixed cells. Overall, aldehyde fixation methods performed significantly better than organic solvents with less severe loss of biochemical information. Aldehyde based fixatives show an altered biochemical content of the cells, attributed to adduct formation, but this can be minimised by optimising fixation temperature, or through removal of adduct formation by detergent-based permeabilization treatments as a second step (at the cost of the loss of other biochemical information). The results showed that organic solvents, on the other hand, lead to a severe loss of cell content, attributed to the loss of membrane integrity after the removal of lipids. Additionally, fixation with aldehydes prior to permeabilization with organic solvents does not provide adequate protection of cytoplasmic content. The use of Raman imaging is ideal for comparing groups of cells in terms of their molecular content, and the results show that aldehyde fixations methods are preferable for studies where the overall molecular content of the samples is important. Although there is no universal fixation method for every application, the results here allow us to provide a few general principles: where spectral similarity to live cells is important, fixation with paraformaldehyde at room temperature is preferable, at the cost of some blebbing and vacuole formation. Where preservation of cellular structure or biomolecular distribution is important, a mix of paraformaldehyde and glutaraldehyde would be more appropriate, but at the cost of some changes to spectral profile, particularly in DNA-related bands.
Analysis of the annual cycle of intensity, extent, and width of the Hadley circulation across a 31-yr period (1979–2009) from all existent reanalyses reveals a good agreement among the datasets. All ...datasets show that intensity is at a maximum in the winter hemisphere and at a minimum in the summer hemisphere. Maximum and minimum values of meridional extent are reached in the respective autumn and spring hemispheres. While considering the horizontal momentum balance, where a weakening of the Hadley cell (HC) is expected in association with a widening, it is shown here that there is no direct relationship between intensity and extent on a monthly time scale.
All reanalyses show an expansion in both hemispheres, most pronounced and statistically significant during summer and autumn at an average rate of expansion of 0.55° decade−1in each hemisphere. In contrast, intensity trends are inconsistent among the datasets, although there is a tendency toward intensification, particularly in winter and spring.
Correlations between the HC and tropical and extratropical large-scale modes of variability suggest interactions where the extent of the HC is influenced by El Niño–Southern Oscillation (ENSO) and the annular modes. The cells tend to shrink (expand) during the warm (cold) phase of ENSO and during the low (high) phase of the annular modes. Intensity appears to be influenced only by ENSO and only during spring for the southern cell and during winter for the northern cell.
We experimentally investigate the nature of 2D phase transitions in a quasi-2D granular fluid. Using a surface decorated with periodically spaced dimples we observe interfacial tension between ...coexisting granular liquid and crystal phases. Measurements of the orientational and translational order parameters and associated susceptibilities indicate that the surface topography alters the order of the phase transition from a two-step continuous one to a first-order liquid-solid one. The interplay of boundary inelasticity and geometry, either order promoting or inhibiting, controls whether it is the granular crystal or the granular fluid which makes contact with the edge. This order induced wetting has important consequences, determining how coexisting phases separate spatially.
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