Hexokinase-2-Linked Glycolytic Overload and Unscheduled Glycolysis—Driver of Insulin Resistance and Development of Vascular Complications of Diabetes

The recent discovery of the glucose-induced stabilization of hexokinase-2 (HK2) to proteolysis in cell dysfunction in model hyperglycemia has revealed a likely key initiating factor contributing to the development of insulin resistance and vascular complications in diabetes. Consequently, the increased flux of glucose metabolism without a change in the expression and activity of glycolytic enzymes produces a wave of increased glycolytic intermediates driving mitochondrial dysfunction and increased reactive oxygen species (ROS) formation, the activation of hexosamine and protein kinase C pathways, the increased formation of methylglyoxal-producing dicarbonyl stress, and the activation of the unfolded protein response. This is called HK2-linked glycolytic overload and unscheduled glycolysis. The conditions required to sustain this are GLUT1 and/or GLUT3 glucose uptake and the expression of HK2. A metabolic biomarker of its occurrence is the abnormally increased deposition of glycogen, which is produced by metabolic channeling when HK2 becomes detached from mitochondria. These conditions and metabolic consequences are found in the vasculature, kidneys, retina, peripheral nerves, and early-stage embryo development in diabetes and likely sustain the development of diabetic vascular complications and embryopathy. In insulin resistance, HK2-linked unscheduled glycolysis may also be established in skeletal muscle and adipose tissue. This may explain the increased glucose disposal by skeletal uptake in the fasting phase in patients with type 2 diabetes mellitus, compared to healthy controls, and the presence of insulin resistance in patients with type 1 diabetes mellitus. Importantly, glyoxalase 1 inducer—trans-resveratrol and hesperetin in combination (tRES-HESP)—corrected HK2-linked glycolytic overload and unscheduled glycolysis and reversed insulin resistance and improved vascular inflammation in overweight and obese subjects in clinical trial. Further studies are now required to evaluate tRES-HESP for the prevention and reversal of early-stage type 2 diabetes and for the treatment of the vascular complications of diabetes.     

Homeostasis and Cancer Initiation: Organoids as Models to Study the Initiation of Gastric Cancer

Gastric cancer represents a significant disease burden worldwide. The factors that initiate cancer are not well understood. Chronic inflammation such as that triggered by H. pylori infection is the most significant cause of gastric cancer. In recent years, organoid cultures developed from human and animal adult stem cells have facilitated great advances in our understanding of gastric homeostasis. Organoid models are now being exploited to investigate the role of host genetics and bacterial factors on proliferation and DNA damage in gastric stem cells. The impact of a chronic inflammatory state on gastric stem cells and the stroma has been less well addressed. This review discusses what we have learned from the use of organoid models to investigate cancer initiation, and highlights questions on the contribution of the microbiota, chronic inflammatory milieu, and stromal cells that can now be addressed by more complex coculture models.     

The effect of a helmet on cognitive performance is,at worst,marginal: A controlled laboratory study

The present study looked at the effect of a helmet on cognitive performance under demanding conditions, so that small effects would become more detectible. Nineteen participants underwent 30 min of continuous visual vigilance, tracking, and auditory vigilance (VTT + AVT), while seated in a warm environment (27.2 (±0.6) °C, humidity 41 (±1)%, and 0.5 (±0.1) m s⁻¹ wind speed). The participants wore a helmet in one session and no helmet in the other, in random order. Comfort and temperature perception were measured at the end of each session. Helmet-wearing was associated with reduced comfort (p = 0.001) and increased temperature perception (p < 0.001), compared to not wearing a helmet. Just one out of nine cognitive parameters showed a significant effect of helmet-wearing (p = .032), disappearing in a post-hoc comparison. These results resolve previous disparate studies to suggest that, although helmets can be uncomfortable, any effect of wearing a helmet on cognitive performance is at worst marginal.     

Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma brucei

There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62 000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel‐compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.     

Tuberculosis reinfection rate as a proportion of total infection rate correlates with the logarithm of the incidence rate: a mathematical model

In a significant number of instances, an episode of tuberculosis can be attributed to a reinfection event. Because reinfection is more likely in high incidence regions than in regions of low incidence, more tuberculosis (TB) cases due to reinfection could be expected in high-incidence regions than in low-incidence regions. Empirical data from regions with various incidence rates appear to confirm the conjecture that, in fact, the incidence rate due to reinfection only, as a proportion of all cases, correlates with the logarithm of the incidence rate, rather than with the incidence rate itself. A theoretical model that supports this conjecture is presented. A Markov model was used to obtain a relationship between incidence and reinfection rates. It was assumed in this model that the rate of reinfection is a multiple, ρ (the reinfection factor), of the rate of first-time infection, λ. The results obtained show a relationship between the proportion of cases due to reinfection and the rate of incidence that is approximately logarithmic for a range of values of the incidence rate typical of those observed in communities across the globe. A value of ρ is determined such that the relationship between the proportion of cases due to reinfection and the logarithm of the incidence rate closely correlates with empirical data. From a purely theoretical investigation, it is shown that a simple relationship can be expected between the logarithm of the incidence rates and the proportions of cases due to reinfection after a prior episode of TB. This relationship is sustained by a rate of reinfection that is higher than the rate of first-time infection and this latter consideration underscores the great importance of monitoring recovered TB cases for repeat disease episodes, especially in regions where TB incidence is high. Awareness of this may assist in attempts to control the epidemic.     

Univariate and default standard unit biases in estimation of body weight and caloric content.

College students estimated the weight of adult women from either photographs or a live presentation by a set of models and estimated the calories in 1 of 2 actual meals. The 2 meals had the same items, but 1 had larger portion sizes than the other. The results suggest: (a) Judgments are biased toward transforming the example in question to the size and/or properties of a “standard” unit. For estimates of body weight, students assigned weights assuming a standard height, even though height information was provided in the photographs or directly present with live models. (b) There is an inclination to focus on 1 aspect or dimension of the stimulus (e.g., for female figures, their width, for meals the identity of the components as opposed to their size) and either devalue or completely ignore another parameter critical for accurate judgment (height, for the case of body weight estimations). That is, students defaulted to a normative unit size and thus treated the stimulus as a representative, categorical, and unvarying example, and focused on only 1 dimension (univariate bias) in making judgments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stigma and barriers to care in soldiers postcombat.

The present study examined the effects of leadership and unit cohesion on mental health stigma and perceived barriers to care. A sample of 680 soldiers from combat support units were surveyed 3 months after their return from combat operations in Iraq. The survey included scales on psychological symptoms and perceptions of leader behaviors and unit cohesion, as well as items assessing stigma and barriers to care. The sample was used to test the independent and interactive effects of leadership and unit cohesion on soldiers’ perceptions of stigma and barriers to care. Analyses yielded significant interaction effects between leadership and cohesion in predicting stigma and barriers to care, while controlling for the effects of mental health symptoms. Soldiers who rated their leaders more highly and who reported higher unit cohesion also reported lower scores on both stigma and perceived barriers to care. Thus, positive leadership and unit cohesion can reduce perceptions of stigma and barriers to care, even after accounting for the relationship between mental health symptoms and these outcomes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Non-destructive assessment of instrumental and sensory tenderness of lamb meat using NIR hyperspectral imaging

The purpose of this study was to develop and test a hyperspectral imaging system (900–1700 nm) to predict instrumental and sensory tenderness of lamb meat. Warner–Bratzler shear force (WBSF) values and sensory scores by trained panellists were collected as the indicator of instrumental and sensory tenderness, respectively. Partial least squares regression models were developed for predicting instrumental and sensory tenderness with reasonable accuracy (R_cv = 0.84 for WBSF and 0.69 for sensory tenderness). Overall, the results confirmed that the spectral data could become an interesting screening tool to quickly categorise lamb steaks in good (i.e. tender) and bad (i.e. tough) based on WBSF values and sensory scores with overall accuracy of about 94.51% and 91%, respectively. Successive projections algorithm (SPA) was used to select the most important wavelengths for WBSF prediction. Additionally, textural features from Gray Level Co-occurrence Matrix (GLCM) were extracted to determine the correlation between textural features and WBSF values.