Transgenic cotton and sterile insect releases synergize eradication of pink bollworm a century after it invaded the United States.

Invasive organisms pose a global threat and are exceptionally difficult to eradicate after they become abundant in their new habitats. We report a successful multitactic strategy for combating the pink bollworm (Pectinophora gossypiella), one of the world's most invasive pests. A coordinated program in the southwestern United States and northern Mexico included releases of billions of sterile pink bollworm moths from airplanes and planting of cotton engineered to produce insecticidal proteins from the bacterium Bacillus thuringiensis (Bt). An analysis of computer simulations and 21 y of field data from Arizona demonstrate that the transgenic Bt cotton and sterile insect releases interacted synergistically to reduce the pest's population size. In Arizona, the program started in 2006 and decreased the pest's estimated statewide population size from over 2 billion in 2005 to zero in 2013. Complementary regional efforts eradicated this pest throughout the cotton-growing areas of the continental United States and northern Mexico a century after it had invaded both countries. The removal of this pest saved farmers in the United States $192 million from 2014 to 2019. It also eliminated the environmental and safety hazards associated with insecticide sprays that had previously targeted the pink bollworm and facilitated an 82% reduction in insecticides used against all cotton pests in Arizona. The economic and social benefits achieved demonstrate the advantages of using agricultural biotechnology in concert with classical pest control tactics.

Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review.

BACKGROUND: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. METHOD: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. RESULTS: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. CONCLUSION: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome.

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities. We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE  < 0.05) and between PSQI and T1w intensities (PFWE  < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001). This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study.

PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.

Evidence in chronic fatigue syndrome for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression.

White matter (WM) involvement in chronic fatigue syndrome (CFS) was assessed using voxel-based regressions of brain MRI against CFS severity scores and CFS duration in 25 subjects with CFS and 25 normal controls (NCs). As well as voxel-based morphometry, a novel voxel-based quantitative analysis of T1 - and T2 -weighted spin-echo (T1w and T2w) MRI signal level was performed. Severity scores included the Bell CFS disability scale and scores based on the 10 most common CFS symptoms. Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores were included as nuisance covariates. By relaxing the threshold for cluster formation, we showed that the T1w signal is elevated with increasing CFS severity in the ventrolateral thalamus, internal capsule and prefrontal WM. Earlier reports of WM volume losses and neuroinflammation in the midbrain, together with the upregulated prefrontal myelination suggested here, are consistent with the midbrain changes being associated with impaired nerve conduction which stimulates a plastic response on the cortical side of the thalamic relay in the same circuits. The T2w signal versus CFS duration and comparison of T2w signal in the CFS group with the NC group revealed changes in the right middle temporal lobe WM, where impaired communication can affect cognitive function. Adjustment for depression markedly strengthened cluster statistics and increased cluster size in both T1w severity regressions, but adjustment for anxiety less so. Thus, depression and anxiety are statistical confounders here, meaning that they contribute variance to the T1w signal in prefrontal WM but this does not correlate with the co-located variance from CFS severity. MRI regressions with depression itself only detected associations with WM volume, also located in prefrontal WM. We propose that impaired reciprocal brain-body and brain-brain communication through the midbrain provokes peripheral and central responses which contribute to CFS symptoms. Although anxiety, depression and CFS may share biological features, the present evidence indicates that CFS is a distinct disorder.

NASHA hyaluronic acid vs. methylprednisolone for knee osteoarthritis: a prospective, multi-centre, randomized, non-inferiority trial.

OBJECTIVE: To compare NASHA hyaluronic acid gel as single-injection intra-articular (IA) treatment for knee osteoarthritis (OA) against methylprednisolone acetate (MPA). DESIGN: This was a prospective, multi-centre, randomized, active-controlled, double-blind, non-inferiority clinical trial. A unique, open-label extension phase (OLE) was undertaken to answer further important clinical questions. Subjects with painful unilateral knee OA were treated and followed for 26 weeks (blinded phase). All patients attending the clinic at 26 weeks were offered NASHA treatment, with a subsequent 26-week follow-up period (extension phase). The primary objective was to show non-inferiority of NASHA vs MPA in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain responder rate (percentage of patients with ≥40% improvement from baseline in WOMAC pain score and an absolute improvement of ≥5 points) at 12 weeks. RESULTS: In total, 442 participants were enrolled. The primary objective was met, with NASHA producing a non-inferior response rate vs MPA at 12 weeks (NASHA: 44.6%; MPA: 46.2%; difference [95% CI]: 1.6% [-11.2%; +7.9%]). Effect size for WOMAC pain, physical function and stiffness scores favoured NASHA over MPA from 12 to 26 weeks. In response to NASHA treatment at 26 weeks, sustained improvements were seen in WOMAC outcomes irrespective of initial treatment. No serious device-related adverse events (AEs) were reported. CONCLUSIONS: This study shows that single-injection NASHA was well tolerated and non-inferior to MPA at 12 weeks. The benefit of NASHA was maintained to 26 weeks while that of MPA declined. An injection of NASHA at 26 weeks conferred long-term improvements without increased sensitivity or risk of complications. STUDY IDENTIFIER: NCT01209364 (www.clinicaltrials.gov).

GLUT1 regulation of the pro-sclerotic mediators of diabetic nephropathy.

Diabetic glomerulosclerosis is characterized by accumulation of extracellular matrix proteins, mesangial expansion, and tubulointerstitial fibrosis. Hyperglycemia accelerates development of the disease, a direct result of increased intracellular glucose availability. The facilitative glucose transporter GLUT1 mediates mesangial cell glucose flux which leads to activation of signaling cascades favoring glomerulosclerosis, including pathways mediated by angiotensin II (Ang II), transforming growth factor ß (TGF-ß), connective tissue growth factor (CTGF), and vascular endothelial growth factor (VEGF). Ang II has both hemodynamic and metabolic effects directly inducing GLUT1 and/or matrix protein synthesis through diacyl glycerol (DAG) or protein kinase C (PKC) induction, mesangial cell stretch, and/or through transactivation of the epidermal growth factor receptor, the platelet-derived growth factor receptor, and the insulin-like growth factor-1 receptor, all of which may stimulate GLUT1 synthesis via an ERK-mediated pathway. Conversely, inhibition of Ang II effects suppresses GLUT1 and cellular glucose uptake. GLUT1-mediated glucose flux leads to metabolism of glucose via glycolysis, with induction of DAG, PKC, TGF-ß1, CTGF and VEGF. VEGF in turn triggers both GLUT1 and matrix synthesis. New roles for GLUT1-mTOR and GLUT1-mechano-growth factor interactions in diabetic glomerulosclerosis have also recently been suggested. Recent mouse models confirmed roles for GLUT1 in vivo in stimulating glomerular growth factor expression, growth factor receptors and development of glomerulosclerosis. GLUT1 may therefore act in concert with cytokines and growth factors to induce diabetic glomerulosclerosis. Further clarification of the pathways involved may prove useful for the therapy of diabetic nephropathy. New directions for investigation are discussed.

Reduced expression of lipoic acid synthase accelerates diabetic nephropathy.

Oxidative stress contributes to the pathogenesis of diabetic nephropathy. In mitochondria, lipoic acid synthase produces α-lipoic acid, an antioxidant and an essential cofactor in α-ketoacid dehydrogenase complexes, which participate in glucose oxidation and ATP generation. Administration of lipoic acid abrogates diabetic nephropathy in animal models, but whether lower production of endogenous lipoic acid promotes diabetic nephropathy is unknown. Here, we crossed mice heterozygous for lipoic acid synthase deficiency (Lias(+/-)) with Ins2(Akita/+) mice, a well characterized model of type 1 diabetes. Double mutant mice had more overt diabetic nephropathy, including microalbuminuria, glomerular basement thickening, mesangial matrix expansion, and hypertension, compared with Lias(+/+)Ins2(Akita/+) controls. We also identified proximal tubules as a major site for generation of superoxide anions during diabetic nephropathy. Mitochondria in proximal tubular cells were particularly sensitive to damage in diabetic mice with reduced lipoic acid production. These results suggest that lipoic acid synthase deficiency increases oxidative stress and accelerates the development of diabetic nephropathy.

Modeling pH and Temperature Effects as Climatic Hazards in Vibrio Vulnificus and Vibrio Parahaemolyticus Planktonic Growth and Biofilm Formation.

Climate-induced stressors, such as changes in temperature, salinity, and pH, contribute to the emergence of infectious diseases. These changes alter geographical constraint, resulting in increased Vibrio spread, exposure, and infection rates, thus facilitating greater Vibrio-human interactions. Multiple efforts have been developed to predict Vibrio exposure and raise awareness of health risks, but most models only use temperature and salinity as prediction factors. This study aimed to better understand the potential effects of temperature and pH on V. vulnificus and V. parahaemolyticus planktonic and biofilm growth. Vibrio strains were grown in triplicate at 25°, 30°, and 37°C in 96 well plates containing Modified Seawater Yeast Extract modified with CaCl2 at pH's ranging from 5 to 9.6. AMiGA software was used to model growth curves using Gaussian process regression. The effects of temperature and pH were evaluated using randomized complete block analysis of variance, and the growth rates of V. parahaemolyticus and V. vulnificus were modeled using the interpolation fit on the MatLab Curve Fitting Toolbox. Different optimal conditions involving temperature and pH were observed for planktonic and biofilm Vibrio growth within- and between-species. This study showed that temperature and pH factors significantly affect Vibrio planktonic growth rates and V. parahaemolyticus biofilm formation. Therefore, pH effects must be added to the Vibrio growth modeling efforts to better predict Vibrio risk in estuarine and coastal zones that can potentially experience the cooccurrence of Vibrio and harmful algal bloom outbreak events.

Nitrate reductase activity of bacteria in saliva of term and preterm infants.

The salivary glands of adults concentrate nitrate from plasma into saliva where it is converted to nitrite by bacterial nitrate reductases. Nitrite can play a beneficial role in adult gastrointestinal and cardiovascular physiology. When nitrite is swallowed, some of it is converted to nitric oxide (NO) in the stomach and may then exert protective effects in the gastrointestinal tract and throughout the body. It has yet to be determined either when newborn infants acquire oral nitrate reducing bacteria or what the effects of antimicrobial therapy or premature birth may be on the bacterial processing of nitrate to nitrite. We measured nitrate and nitrite levels in the saliva of adults and both preterm and term human infants in the early weeks of life. We also measured oral bacterial reductase activity in the saliva of both infants and adults, and characterized the species of nitrate reducing bacteria present. Oral bacterial conversion of nitrate to nitrite in infants was either undetectable or markedly lower than the conversion rates of adults. No measurable reductase activity was found in infants within the first two weeks of life, despite the presence of oral nitrate reducing bacteria such as Actinomyces odontolyticus, Veillonella atypica, and Rothia mucilaginosa. We conclude that relatively little nitrite reaches the infant gastrointestinal tract due to the lack of oral bacterial nitrate reductase activity. Given the importance of the nitrate-nitrite-NO axis in adults, the lack of oral nitrate-reducing bacteria in infants may be relevant to the vulnerability of newborns to hypoxic stress and gastrointestinal tract pathologies.

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis.

To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel-based regressions against clinical scores. Using SPM5 we performed voxel-based morphometry (VBM) and analysed T(1) - and T(2) -weighted spin-echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24-h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T(1) -weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).

Influence of glucosamine on glomerular mesangial cell turnover: implications for hyperglycemia and hexosamine pathway flux.

Cells exposed to high glucose may undergo hypertrophy, proliferation, and apoptosis, but the role of hexosamine flux in mediating these effects has not been fully elucidated. Accordingly, we studied the effects of glucose and glucosamine on rat glomerular mesangial cells (MC) turnover. Compared with physiological glucose (5.6 mM), treatment with high glucose (25 mM) for 24 h stimulated MC proliferation, an effect that was mimicked by exposure to low concentrations of glucosamine (0.05 mM). The percentage of cells in G(0)/G(1) phase of the cell cycle was reduced with a concomitant increase of the number of cells in G(2)/M phase. Proliferating cell nuclear antigen, phosphorylated mammalian target of rapamycin [phospho-mTOR (Ser(2448))], and total regulatory-associated protein of mTOR were increased by high glucose and glucosamine treatment. Inhibition of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme for hexosamine flux, with 6-diazo-5-oxonorleucine (10 muM) and of mTOR with rapamycin both attenuated glucose-mediated MC proliferation. Higher glucosamine concentrations (0.25-10 mM) caused MC apoptosis after 48 h, and, in addition, GFAT overexpression also increased MC apoptosis (TdT-dUTP nick end-labeling-positive cells: 3.8 +/- 0.3 vs. 1.1 +/- 0.2% for empty vector; P < 0.05). Hence, hexosamine flux is an important determinant of MC proliferation and apoptosis. The proliferative response to high glucose and hexosamine flux is rapamycin-sensitive, suggesting that this effect is associated with signaling through rapamycin-sensitive mTOR complex 1 (mTORC1).

Behavior of carbon dioxide and other volatiles on Mars.

We have found that a rather simple thermal model of the Martian surface, in combination with current observations of the atmospheric composition, points strongly toward the conclusion that the polar caps of Mars consist almost entirely of frozen CO(2). This study was based upon the following principal assumptions. 1) Carbon dioxide is a major constituent of the Martian atmosphere. 2) The blanketing effect of the atmosphere is small, and due principally to the absorption band of CO(2) near 15 microns. 3) Lateral and convective heat transfer by the atmosphere is negligible. 4) The far-infrared emissivity of the Martian soil and of solid CO(2) are near unity. 5) The reflectivities of the soil and of solid CO(2) in the visible part of the spectrum are about 0.15 and 0.65, respectively. 6) Values for soil conductivity, density, and specific heat are those characteristic of powdered minerals at low gas pressure. 7) Water is a minor constituent of the Martian atmosphere, the maximum total amount in the atmosphere being 10 to 30 X 1O(-4) g cm(-2). In addition, several simplifications were made, which might have significant effects but should not alter our principal conclusions. Among these are the following. 1) Local blanketing or snowfall effects due to clouds or polar haze were ignored. 2) Dark and light areas were not differentiated in this study, although Sinton and Strong (6) have observed temperature differences between such areas. 3) The effects of local topography and microrelief were neglected. We believe that these must have quite significant effects at the higher latitudes, especially in connection with the evaporation of the remanent south polar cap. 4) Variation of reflectivity with angle of incidence of the sunlight was neglected. 5) Temperature dependence of soil conductivity and specific heat was ignored. 6) Effects of saturation of the soil by ice upon the thermal properties of the soil were neglected. Although in our main investigation we used certain specific values for the various relevant parameters, we also tested the effects of moderate changes in these quantities. Specifically, the soil conductivity was varied by a factor of 3, the albedo and emissivity of the surface were changed by 15 to 20 percent, and the effects of a gross amount of atmospheric blanketing were studied, as described. Only the last of these variations had any significant effect on the model, and other results of the atmospheric blanketing were in disagreement with other physical observations of the planet. Consequently, we find it difficult to avoid the conclusion that CO(2) must condense in large amounts relative to H(2)0. The main conclusions indicated by this study are the following. 1) The atmosphere and frost caps of Mars represent a single system with CO(2) as the only active phase. 2) The appearance and disappearance of the polar caps are adequately explained on the presumption that they are composed almost entirely of solid CO(2) with perhaps an occasional thin coating of water ice. 3) If the currently reported water-vapor observations are correct, water-ice permafrost probably exists under large regions of the planet at polar and temperate latitudes. 4) The geochemically anomalous enrichment of CO(2) relative to N(2) in the present Martian atmosphere may be a result of selective trapping of CO(2) in the solid phase at and under the surface. 5) If the basic evaporation and condensation mechanisms for CO(2) and H(2)O discussed in this article are correct, the possible migration of volatile organic compounds away from the warm temperate regions of the planet and their possible accumulation in the polar regions need to be carefully considered.

Mariner 9 television reconnaissance of Mars and its satellites: preliminary results.

At orbit insertion on 14 November 1971 the Martian surface was largely obscured by a dust haze with an extinction optical depth that ranged from near unity in the south polar region to probably greater than 2 over most of the planet. The only features clearly visible were the south polar cap, one dark, spot in Nix Olympica, and three dark spots in the Tharsis region. During the third week the atmosphere began to clear and surface visibility improved, but contrasts remained a fraction of their normal value. Each of the dark spots that apparently protrude through most of the dust-filled atmosphere has a crater or crater complex in its center. The craters are rimless and have featureless floors that, in the crater complexes, are at different levels. The largest crater within the southernmost spot is approximately 100 kilometers wide. The craters apparently were formed by subsidence and resemble terrestrial calderas. The south polar cap has a regular margin, suggsting very flat topography. Two craters outside the cap have frost on their floors; an apparent crater rim within the cap is frost free, indicating preferentia loss of frost from elevated ground. If this is so then the curvilinear streaks, which were frost covered in 1969 and are now clear of frost, may be low-relief ridges. Closeup pictures of Phobos and Deimos show that Phobos is about 25 +/-5 by 21 +/-1 kilometers and Deimos is about 13.5 +/- 2 by 12.0 +/-0.5 kilometers. Both have irregular shapes and are highly cratered, with some craters showing raised rims. The satellites are dark objects with geometric albedos of 0.05.

Intra brainstem connectivity is impaired in chronic fatigue syndrome.

In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.

In vitro measurements of hemodynamic forces and their effects on endothelial cell mechanics at the sub-cellular level.

This paper presents micro-particle tracking velocimetry measurements over cultured bovine aortic endothelial cell monolayers in microchannels. The objective was to quantify fluid forces and cell morphology at the sub-cellular scale for monolayers subjected to steady shear rates of 5, 10, and 20 dyn/cm2. The ultimate goal of this study was to develop an experimental methodology for in vitro detailed study of physiologically realistic healthy and diseased conditions. Cell topography, shear stress, and pressure distributions were calculated from sets of velocity fields made in planes parallel to the microchannel wall. For each experiment, measurements were made in 3 h intervals for 18 h. It was found that there is a three-dimensional change in cell morphology as a result of applied shear stress. That is, cells flatten and become more wedge shaped in the stream direction while conserving volume by spreading laterally, i.e., in the cross-stream direction. These changes in cell morphology are directly related to local variations in fluid loading, i.e., shear stress and pressure. This paper describes the first flow measurements over a confluent layer of endothelial cells that are spatially resolved at the sub-cellular scale with a simultaneous temporal resolution to quantify the response of cells to fluid loading.

Decreased Connectivity and Increased Blood Oxygenation Level Dependent Complexity in the Default Mode Network in Individuals with Chronic Fatigue Syndrome.

The chronic fatigue syndrome (CFS)/myalgic encephalomyelitis is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) to understand the pathophysiology of CFS and to identify potential biomarkers. Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798 sec, we evaluated the DMN using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps, and complexity of activity. General linear model univariate analysis was used for intergroup comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores. BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (p < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (p < 0.05) during resting state, whereas during task mPFC-left IPL and mPFC-PCC were weaker (p < 0.05). The DFCs between the DMN hubs were more complex in CFS (p < 0.05) during task. Each of these differences accounted for 7-11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potentially used as a diagnostic biomarker for CFS.

Hyperintense sensorimotor T1 spin echo MRI is associated with brainstem abnormality in chronic fatigue syndrome.

We recruited 43 Chronic Fatigue Syndrome (CFS) subjects who met Fukuda criteria and 27 healthy controls and performed 3T MRI T1 and T2 weighted spin-echo (T1wSE and T2wSE) scans. T1wSE signal follows T1 relaxation rate (1/T1 relaxation time) and responds to myelin and iron (ferritin) concentrations. We performed MRI signal level group comparisons with SPM12. Spatial normalization after segmentation was performed using T2wSE scans and applied to the coregistered T1wSE scans. After global signal-level normalization of individual scans, the T1wSE group comparison detected decreased signal-levels in CFS in a brainstem region (cluster-based inference controlled for family wise error rate, PFWE= 0.002), and increased signal-levels in large bilateral clusters in sensorimotor cortex white matter (cluster PFWE < 0.0001). Moreover, the brainstem T1wSE values were negatively correlated with the sensorimotor values for both CFS (R2 = 0.31, P = 0.00007) and healthy controls (R2 = 0.34, P = 0.0009), and the regressions were co-linear. This relationship, previously unreported in either healthy controls or CFS, in view of known thalamic projection-fibre plasticity, suggests brainstem conduction deficits in CFS may stimulate the upregulation of myelin in the sensorimotor cortex to maintain brainstem - sensorimotor connectivity. VBM did not find group differences in regional grey matter or white matter volumes. We argued that increased T1wSE observed in sensorimotor WM in CFS indicates increased myelination which is a regulatory response to deficits in the brainstem although the causality cannot be tested in this study. Altered brainstem myelin may have broad consequences for cerebral function and should be a focus of future research.