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1.  Ethanol effect on metabolic activity of the ethalogenic fungus Fusarium oxysporum 
BMC Biotechnology  2015;15:15.
Background
Fusarium oxysporum is a filamentous fungus which has attracted a lot of scientific interest not only due to its ability to produce a variety of lignocellulolytic enzymes, but also because it is able to ferment both hexoses and pentoses to ethanol. Although this fungus has been studied a lot as a cell factory, regarding applications for the production of bioethanol and other high added value products, no systematic study has been performed concerning its ethanol tolerance levels.
Results
In aerobic conditions it was shown that both the biomass production and the specific growth rate were affected by the presence of ethanol. The maximum allowable ethanol concentration, above which cells could not grow, was predicted to be 72 g/L. Under limited aeration conditions the ethanol-producing capability of the cells was completely inhibited at 50 g/L ethanol. The lignocellulolytic enzymatic activities were affected to a lesser extent by the presence of ethanol, while the ethanol inhibitory effect appears to be more severe at elevated temperatures. Moreover, when the produced ethanol was partially removed from the broth, it led to an increase in fermenting ability of the fungus up to 22.5%. The addition of F. oxysporum’s system was shown to increase the fermentation of pretreated wheat straw by 11%, in co-fermentation with Saccharomyces cerevisiae.
Conclusions
The assessment of ethanol tolerance levels of F. oxysporum on aerobic growth, on lignocellulolytic activities and on fermentative performance confirmed its biotechnological potential for the production of bioethanol. The cellulolytic and xylanolytic enzymes of this fungus could be exploited within the biorefinery concept as their ethanol resistance is similar to that of the commercial enzymes broadly used in large scale fermentations and therefore, may substantially contribute to a rational design of a bioconversion process involving F. oxysporum. The SSCF experiments on liquefied wheat straw rich in hemicellulose indicated that the contribution of the metabolic system of F. oxysporum in a co-fermentation with S. cerevisiae may play a secondary role.
doi:10.1186/s12896-015-0130-3
PMCID: PMC4417268  PMID: 25887038
Bioethanol; Ethanol inhibition; Ethanol tolerance; Ethanol removal; Fusarium oxysporum
2.  Dose and time response of ruminally infused algae on rumen fermentation characteristics, biohydrogenation and Butyrivibrio group bacteria in goats 
Background
Micro-algae could inhibit the complete rumen BH of dietary 18-carbon unsaturated fatty acid (UFAs). This study aimed to examine dose and time responses of algae supplementation on rumen fermentation, biohydrogenation and Butyrivibrio group bacteria in goats.
Methods
Six goats were used in a repeated 3 × 3 Latin square design, and offered a fixed diet. Algae were infused through rumen cannule with 0 (Control), 6.1 (L-Alg), or 18.3 g (H-Alg) per day. Rumen contents were sampled on d 0, 3, 7, 14 and 20.
Results
H-Alg reduced total volatile fatty acid concentration and acetate molar proportion (P < 0.05), and increased propionate molar proportion (P < 0.05), whereas L-Alg had no effect on rumen fermentation. Changes in proportions of acetate and propionate in H-Alg were obvious from d 7 onwards and reached the largest differences with the control on d 14. Algae induced a dose-dependent decrease in 18:0 and increased trans-18:1 in the ruminal content (P < 0.05). H-Alg increased the concentrations of t9, t11-18:2 and t11, c15-18:2 (P < 0.05). L-Alg only seemed to induce a transient change in 18-carbon isomers, while H-Alg induced a rapid elevation, already obvious on d 3, concentrations of these fatty acid rose in some cases again on d 20. Algae had no effect on the abundances of Butyrivibrio spp. and Butyrivibrio proteoclasticus (P > 0.10), while H-Alg reduced the total bacteria abundance (P < 0.05). However, this was induced by a significant difference between control and H-Alg on d 14 (-4.43 %). Afterwards, both treatments did not differ as increased variation in the H-Alg repetitions, with in some cases a return of the bacterial abundance to the basal level (d 0).
Conclusions
Changes in rumen fermentation and 18-carbon UFAs metabolism in response to algae were related to the supplementation level, but there was no evidence of shift in ruminal biohydrogenation pathways towards t10-18:1. L-Alg mainly induced a transient effect on rumen biohydrogenation of 18-carbon UFAs, while H-Alg showed an acute inhibition and these effects were not associated with the known hydrogenating bacteria.
Electronic supplementary material
The online version of this article (doi:10.1186/s40104-016-0080-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s40104-016-0080-1
PMCID: PMC4823909  PMID: 27057310
Algae; Biohydrogenation; Goat; Hydrogenating bacteria
3.  Epidemiology of ischemic placental disease: A focus on preterm gestations 
Seminars in perinatology  2014;38(3):133-138.
Preeclampsia, placental abruption, and intrauterine growth restriction (IUGR) have collectively been termed ischemic placental disease (IPD) due to a suspected common biological pathway involving poor placentation in early pregnancy and subsequent placental insufficiency. Despite decades of research, the etiologies of these conditions remain largely unknown and preventive and therapeutic strategies are lacking. It has been suggested that the underpinnings of IPD lie primarily in preterm gestations and that classification of these conditions based on the gestational age at onset will facilitate etiologic research. The purpose of this review is to describe our current knowledge regarding the risk factors, co-occurrence, and recurrence of the conditions of IPD with a specific focus on the preterm gestational window.
doi:10.1053/j.semperi.2014.03.004
PMCID: PMC4824536  PMID: 24836824
Preeclampsia; Placental abruption; Small for gestational age; Early onset; Preterm
4.  Disentangling effects of abiotic factors and biotic interactions on cross-taxon congruence in species turnover patterns of plants, moths and beetles 
Scientific Reports  2016;6:23511.
High cross-taxon congruence in species diversity patterns is essential for the use of surrogate taxa in biodiversity conservation, but presence and strength of congruence in species turnover patterns, and the relative contributions of abiotic environmental factors and biotic interaction towards this congruence, remain poorly understood. In our study, we used variation partitioning in multiple regressions to quantify cross-taxon congruence in community dissimilarities of vascular plants, geometrid and arciinid moths and carabid beetles, subsequently investigating their respective underpinning by abiotic factors and biotic interactions. Significant cross-taxon congruence observed across all taxon pairs was linked to their similar responses towards elevation change. Changes in the vegetation composition were closely linked to carabid turnover, with vegetation structure and associated microclimatic conditions proposed causes of this link. In contrast, moth assemblages appeared to be dominated by generalist species whose turnover was weakly associated with vegetation changes. Overall, abiotic factors exerted a stronger influence on cross-taxon congruence across our study sites than biotic interactions. The weak congruence in turnover observed particularly between plants and moths highlights the importance of multi-taxon approaches based on groupings of taxa with similar turnovers, rather than the use of single surrogate taxa or environmental proxies, in biodiversity assessments.
doi:10.1038/srep23511
PMCID: PMC4817036  PMID: 27032533
5.  Disparities in Treatment of Patients with Inoperable Stage I Non-Small Cell Lung Cancer: A Population-Based Analysis 
Background
Patients unable to receive surgery for stage I non-small cell lung cancer (NSCLC) can undergo conventional radiotherapy (ConvRT), stereotactic body radiotherapy (SBRT), or no treatment (NoTx). This study assessed patterns of care and disparities in the receipt of each of these treatments.
Methods
The study included patients in the National Cancer Database from 2003-2011 with T1-T2N0M0 inoperable lung cancer (n= 39,822). Logistic regressions were performed to determine predictors of receiving any radiation vs. NoTx and for receiving SBRT vs. ConvRT.
Findings
Treatment with radiation was significantly less likely in blacks (OR 0.65) and Hispanics (OR 0.42) compared to whites. Treatment with SBRT vs ConvRT was more likely in an academic research program (OR: 2.62) and a high-volume facility (OR: 7.00) compared to community cancer programs or low-volume facilities. In 2011, use of SBRT, ConvRT and NoTx was 25%, 28% and 46% for patients in a community cancer center versus 68%, 11% and 21%, respectively, in an academic center (p < 0.0001).
Conclusion
There were marked institutional and socioeconomic variations in the treatment of inoperable stage I NSCLC. These results suggest that removal of barriers to receive radiation therapy and particularly improved access to SBRT may meaningfully improve survival in this disease.
doi:10.1097/JTO.0000000000000418
PMCID: PMC4807970  PMID: 25371079
Stereotactic Body Radiotherapy; Lung Cancer; Stage I; Radiation
6.  Activation of Cannabinoid Type Two Receptors (CB2) Diminish Inflammatory Responses in Macrophages and Brain Endothelium 
Chronic neuroinflammatory disorders (such as HIV associated neurodegeneration) require treatment that decreases production of inflammatory factors by activated microglia and macrophages and protection of blood brain barrier (BBB) injury secondary to activation of brain endothelium. Cannabioid type 2 receptor (CB2) is highly expressed on macrophages and brain microvasular enndothelial cells (BMVEC) and is upregulated in inflammation and HIV infection. It has been shown that CB2 activation dampened inflammatory responses in macrophages and BMVEC. In this study, we assessed by PCR array the expression of a wide range of genes increased in macrophages and BMVEC in inflammation. TNFα treatment upregulated 33 genes in primary human BMVEC, and two highly selective CB2 agonists diminished expression of 31 and 32 genes. These results were confirmed by functional assays (BBB protection after inflammatory insult and decreased migration of monocytes across BMVEC monolayers after CB2 stimulation). Similarly, CB2 stimulation in primary human macrophages led to the suppression of 35 genes out of the 50 genes upregulated by LPS. Such changes in gene expression paralleled diminished secretion of proinflammatory factors. These results indicate the potential utility of CB2 agonists for the treatment of neuroinflammation.
doi:10.1007/s11481-015-9591-3
PMCID: PMC4795159  PMID: 25666933
Cannabinoid type 2 receptor; Neuroinflammation; Brain endothelial cell; Macrophage; Blood brain barrier
7.  Infections and Brain Development 
Obstetrical & gynecological survey  2015;70(10):644-655.
Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner.
doi:10.1097/OGX.0000000000000236
PMCID: PMC4795171  PMID: 26490164
8.  Indentation of a rigid sphere into an elastic substrate with surface tension and adhesion 
The surface tension of compliant materials such as gels provides resistance to deformation in addition to and sometimes surpassing that owing to elasticity. This paper studies how surface tension changes the contact mechanics of a small hard sphere indenting a soft elastic substrate. Previous studies have examined the special case where the external load is zero, so contact is driven by adhesion alone. Here, we tackle the much more complicated problem where, in addition to adhesion, deformation is driven by an indentation force. We present an exact solution based on small strain theory. The relation between indentation force (displacement) and contact radius is found to depend on a single dimensionless parameter: ω=σ(μR)−2/3((9π/4)Wad)−1/3, where σ and μ are the surface tension and shear modulus of the substrate, R is the sphere radius and Wad is the interfacial work of adhesion. Our theory reduces to the Johnson–Kendall–Roberts (JKR) theory and Young–Dupre equation in the limits of small and large ω, respectively, and compares well with existing experimental data. Our results show that, although surface tension can significantly affect the indentation force, the magnitude of the pull-off load in the partial wetting liquid-like limit is reduced only by one-third compared with the JKR limit and the pull-off behaviour is completely determined by ω.
doi:10.1098/rspa.2014.0727
PMCID: PMC4353052  PMID: 25792953
adhesion; indentation; contact mechanics; surface tension
9.  Channel based generating function approach to the stochastic Hodgkin-Huxley neuronal system 
Scientific Reports  2016;6:22662.
Internal and external fluctuations, such as channel noise and synaptic noise, contribute to the generation of spontaneous action potentials in neurons. Many different Langevin approaches have been proposed to speed up the computation but with waning accuracy especially at small channel numbers. We apply a generating function approach to the master equation for the ion channel dynamics and further propose two accelerating algorithms, with an accuracy close to the Gillespie algorithm but with much higher efficiency, opening the door for expedited simulation of noisy action potential propagating along axons or other types of noisy signal transduction.
doi:10.1038/srep22662
PMCID: PMC4778126  PMID: 26940002
10.  Dual pathology of the submandibular gland: plasmacytoma and pleomorphic adenoma 
BMJ Case Reports  2014;2014:bcr2013202463.
Synchronous tumours of different histological types involving the salivary gland are very rare. There have been cases reported in the literature of such tumours occurring in the parotid gland. A 52-year-old man presented with a 4-year history of gradually increasing painless swelling in the right submandibular region. The ultrasound scan of the neck showed features suggestive of a submandibular sialadenitis. The right submandibular gland was then surgically excised and sent for histopathological examination. The features showed a unique dual pathology of the submandibular gland, that is, a plasmacytoma and a pleomorphic adenoma. Such a synchronous double pathology involving the submandibular gland has not been reported in the literature. A review of the literature suggests a good prognosis for the extramedullary plasmacytoma, provided multiple myeloma is ruled out. In 18 months of follow-up, the patient has been asymptomatic with a negative myeloma workup.
doi:10.1136/bcr-2013-202463
PMCID: PMC3948063  PMID: 24591383
11.  Lipoprotein Concentration, Particle Number, Size and Cholesterol Efflux Capacity are associated with Mitochondrial Oxidative Stress and Function in an HIV Positive Cohort 
Atherosclerosis  2014;239(1):50-54.
Background
Association of lipoprotein particle size/number and HDL function with mitochondrial oxidative stress and function may underlie the excess cardiovascular (CVD) risk in HIV.
Methods and Results
Among HIV infected individuals on stable highly active antiretroviral therapy, we related standard and novel lipid measures [plasma total cholesterol, triglycerides, HDL-C, LDL-C, lipoprotein particle (-P) subclass size and number and HDL function (via cholesterol-efflux capacity)] with oxidative stress [peripheral blood mononuclear cell’s mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG)] and function markers [oxidative phosphorylation (OXPHOS) NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activities]. Multivariable-adjusted logistic and linear regression analyses were employed adjusting for age, gender, CD4 nadir, viral load, smoking, diabetes, HOMA-IR, hypertension and lipid medications. Among 150 HIV-infected persons (mean age 52 years, 12% women, median CD4 count 524 cell/mm3), low HDL-C and high total cholesterol/HDL-C ratio were related to PBMC 8-oxo-deoxyguanine (p=0.01 and 0.02 respectively). Large HDL-P and HDL-P size were inversely related to PBMC 8-oxo-deoxyguanine (p=0.04). Small LDL-P (p=0.01) and total LDL-P (p=0.01) were related to decreased OXPHOS Complex I activity. LDL-P was related to decreased OXPHOS Complex IV activity (p=0.02). Cholesterol efflux capacity was associated with increased OXPHOS Complex IV activity.
Conclusions
HDL concentration and particle size and number are related to decreased PBMC mitochondrial oxidative stress whereas HDL function is positively related to mitochondrial oxidative function. The association we find between atherogenic lipoprotein profile and increased oxidative stress and function suggests these pathways may be important in the pathogenesis of cardiometabolic disease in HIV disease.
doi:10.1016/j.atherosclerosis.2014.12.005
PMCID: PMC4370782  PMID: 25574857
atherosclerosis; cardiovascular disease; lipids; NMR spectroscopy; oxidative phosphorylation; cholesterol efflux capacity; HDL
12.  Recent Progress in Cell Reprogramming Technology for Cell Transplantation Therapy 
Neurologia Medico-Chirurgica  2016;56(3):97-101.
The discovery of induced pluripotent stem (iPS) cells opened the gate for reprogramming technology with which we can change the cell fate through overexpression of master transcriptional factors. Now we can prepare various kinds of neuronal cells directly induced from somatic cells. It has been reported that overexpression of a neuron-specific transcriptional factors might change the cell fate of endogenous astroglia to neuronal cells in vivo. In addition, some research groups demonstrated that chemical compound can induce chemical-induced neuronal cells, without transcriptional factors overexpression. In this review, we briefly review recent progress in the induced neuronal (iN) cells, and discuss the possibility of application for cell transplantation therapy.
doi:10.2176/nmc.ra.2015-0309
PMCID: PMC4791309  PMID: 26876902
induced pluripotent stem cells; induced neuronal cells; in vivo direct reprogramming; chemical-induced neuronal cells; stroke
13.  Celastrol protects mouse retinas from bright light-induced degeneration through inhibition of oxidative stress and inflammation 
Background
Photoreceptor death leads to vision impairment in several retinal degenerative disorders. Therapies protecting photoreceptor from degeneration remain to be developed. Anti-inflammation, anti-oxidative stress, and neuroprotective effects of celastrol have been demonstrated in a variety of disease models. The current study aimed to investigate the photoreceptor protective effect of celastrol.
Methods
Bright light-induced retinal degeneration in BALB/c mice was used, and morphological, functional, and molecular changes of retina were evaluated in the absence and presence of celastrol treatment.
Results
Significant morphological and functional protection was observed as a result of celastrol treatment in bright light-exposed BALB/c mice. Celastrol treatment resulted in suppression of cell death in photoreceptor cells, alleviation of oxidative stress in the retinal pigment epithelium and photoreceptors, downregulation of retinal expression of proinflammatory genes, and suppression of microglia activation and gliosis in the retina. Additionally, leukostasis was found to be induced in the retinal vasculature in light-exposed BALB/c mice, which was significantly attenuated by celastrol treatment. In vitro, celastrol attenuated all-trans-retinal-induced oxidative stress in cultured APRE19 cells. Moreover, celastrol treatment significantly suppressed lipopolysaccharides-stimulated expression of proinflammatory genes in both APRE19 and RAW264.7 cells.
Conclusions
The results demonstrated for the first time that celastrol prevents against light-induced retinal degeneration through inhibition of retinal oxidative stress and inflammation.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0516-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0516-8
PMCID: PMC4769581  PMID: 26920853
14.  Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation 
Background
Conditions of inflammatory tissue distress are associated with high extracellular levels of adenosine, due to increased adenosine triphosphate (ATP) degradation upon cellular stress or the release of extracellular ATP upon cell death, which can be degraded to adenosine by membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is recognised to mediate anti-inflammatory effects via the adenosine A2a receptor (A2aR), as shown in experimental models of arthritis. Here, using pharmacological interventions and genetic inactivation, we investigated the roles of A2aR in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).
Methods
We used two independent mouse EAE variants, i.e. active immunization in C57BL/6 with myelin oligodendrocyte glycoprotein (MOG)35-55 or transfer-EAE by proteolipid protein (PLP)139-155-stimulated T lymphocytes and EAE in mice treated with A2aR-agonist CGS21680 at different stages of disease course and in mice lacking A2aR (A2aR−/−) compared to direct wild-type littermates. In EAE, we analysed myelin-specific proliferation and cytokine synthesis ex vivo, as well as inflammation and demyelination by immunohistochemistry. In vitro, we investigated the effect of A2aR on migration of CD4+ T cells, macrophages and microglia, as well as the impact of A2aR on phagocytosis of macrophages and microglia. Statistical tests were Mann-Whitney U and Student’s t test.
Results
We found an upregulation of A2aR in the central nervous system (CNS) in EAE, predominantly detected on T cells and macrophages/microglia within the inflamed tissue. Preventive EAE treatment with A2aR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease, while application of the same agonist after disease onset exacerbated non-remitting EAE progression and resulted in more severe tissue destruction. Accordingly, A2aR-deficient mice showed accelerated and exacerbated disease manifestation with increased frequencies of IFN-γ-, IL-17- and GM-CSF-producing CD4+ T helper cells and higher numbers of inflammatory lesions in the early stage. However, EAE quickly ameliorated and myelin debris accumulation was lower in A2aR−/− mice. In vitro, activation of A2aR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4+ T cells, macrophages and primary microglia.
Conclusions
A2aR activation exerts a complex pattern in chronic autoimmune neurodegeneration: while providing anti-inflammatory effects on T cells and thus protection at early stages, A2aR seems to play a detrimental role during later stages of disease and may thus contribute to sustained tissue damage within the inflamed CNS.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0512-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0512-z
PMCID: PMC4768407  PMID: 26920550
Adenosine; Multiple sclerosis; Experimental autoimmune encephalomyelitis
15.  Active site specificity profiling datasets of matrix metalloproteinases (MMPs) 1, 2, 3, 7, 8, 9, 12, 13 and 14 
Data in Brief  2016;7:299-310.
The data described provide a comprehensive resource for the family-wide active site specificity portrayal of the human matrix metalloproteinase family. We used the high-throughput proteomic technique PICS (Proteomic Identification of protease Cleavage Sites) to comprehensively assay 9 different MMPs. We identified more than 4300 peptide cleavage sites, spanning both the prime and non-prime sides of the scissile peptide bond allowing detailed subsite cooperativity analysis. The proteomic cleavage data were expanded by kinetic analysis using a set of 6 quenched-fluorescent peptide substrates designed using these results. These datasets represent one of the largest specificity profiling efforts with subsequent structural follow up for any protease family and put the spotlight on the specificity similarities and differences of the MMP family. A detailed analysis of this data may be found in Eckhard et al. (2015) [1]. The raw mass spectrometry data and the corresponding metadata have been deposited in PRIDE/ProteomeXchange with the accession number PXD002265.
doi:10.1016/j.dib.2016.02.036
PMCID: PMC4777984  PMID: 26981551
Matrix metalloproteinases; MMPs; PICS; Proteomics; Quenched fluorescence; Specificity profiling; Cleavage sites
17.  Early Developmental Perturbations in a Human Stem Cell Model of MODY5/HNF1B Pancreatic Hypoplasia 
Stem Cell Reports  2016;6(3):357-367.
Summary
Patients with an HNF1BS148L/+ mutation (MODY5) typically exhibit pancreatic hypoplasia. However, the molecular mechanisms are unknown due to inaccessibility of patient material and because mouse models do not fully recapitulate MODY5. Here, we differentiated MODY5 human-induced pluripotent stem cells (hiPSCs) into pancreatic progenitors, and show that the HNF1BS148L/+ mutation causes a compensatory increase in several pancreatic transcription factors, and surprisingly, a decrease in PAX6 pancreatic gene expression. The lack of suppression of PDX1, PTF1A, GATA4, and GATA6 indicates that MODY5-mediated pancreatic hypoplasia is mechanistically independent. Overexpression studies demonstrate that a compensatory increase in PDX1 gene expression is due to mutant HNF1BS148L/+ but not wild-type HNF1B or HNF1A. Furthermore, HNF1B does not appear to directly regulate PAX6 gene expression necessary for glucose tolerance. Our results demonstrate compensatory mechanisms in the pancreatic transcription factor network due to mutant HNF1BS148L/+ protein. Thus, patients typically develop MODY5 but not neonatal diabetes despite exhibiting pancreatic hypoplasia.
Graphical Abstract
Highlights
•HNF1BS148L/+ mutation elicits a compensatory increase in DE and pancreatic genes•MODY5-mediated pancreatic hypoplasia is independent of PDX1, PTF1A, GATA4, and GATA6•HNF1BS148L mutation directly causes a compensatory increase in PDX1 gene expression•HNF1BS148L/+ mutation limits PAX6 expression and consequently leads to MODY5
Kulkarni, Teo, and colleagues differentiated MODY5-hiPSCs into pancreatic progenitors and demonstrated that HNF1BS148L/+ mutation elicits a compensatory mechanism in the pancreatic transcription factor network. They report that MODY5-mediated pancreatic hypoplasia is independent of PDX1, PTF1A, GATA4, and GATA6. In addition, a decrease in PAX6 gene expression may lead to MODY5 development.
doi:10.1016/j.stemcr.2016.01.007
PMCID: PMC4788763  PMID: 26876668
18.  Decline in Tuberculosis among Mexico-Born Persons in the United States, 2000–2010 
Background
In 2010, Mexico was the most common (22.9%) country of origin for foreign-born persons with tuberculosis in the United States, and overall trends in tuberculosis morbidity are substantially influenced by the Mexico-born population.
Objectives
To determine the risk of tuberculosis disease among Mexico-born persons living in the United States.
Methods
Using data from the U.S. National Tuberculosis Surveillance System and the American Community Survey, we examined tuberculosis case counts and case rates stratified by years since entry into the United States and geographic proximity to the United States–Mexico border. We calculated trends in case rates over time measured by average annual percent change.
Results
The total tuberculosis case count (−14.5%) and annual tuberculosis case rate (average annual percent change −5.1%) declined among Mexico-born persons. Among those diagnosed with tuberculosis less than 1 year since entry into the United States (newly arrived persons), there was a decrease in tuberculosis cases (−60.4%), no change in tuberculosis case rate (average annual percent change of 0.0%), and a decrease in population (−60.7%). Among those living in the United States for more than 5 years (non-recently arrived persons), there was an increase in tuberculosis cases (+3.4%), a decrease in tuberculosis case rate (average annual percent change of −4.9%), and an increase in population (+62.7%). In 2010, 66.7% of Mexico-born cases were among non–recently arrived persons, compared with 51.1% in 2000. Although border states reported the highest proportions (>15%) of tuberculosis cases that were Mexico-born, the highest Mexico-born–specific tuberculosis case rates (>20/100,000 population) were in states in the eastern and southeastern regions of the United States.
Conclusions
The decline in tuberculosis morbidity among Mexico-born persons may be attributed to fewer newly arrived persons from Mexico and lower tuberculosis case rates among non–recently arrived Mexico-born persons. The extent of the decline was dampened by an unchanged tuberculosis case rate among newly arrived persons from Mexico and a large increase in the non–recently arrived Mexico-born population. If current trends continue, tuberculosis morbidity among Mexico-born persons will be increasingly driven by those who have been living in the United States for more than 5 years.
doi:10.1513/AnnalsATS.201402-065OC
PMCID: PMC4747416  PMID: 24708206
tuberculosis; emigration; immigration; Hispanic Americans; Mexican Americans
19.  Blood protein concentrations in the first two postnatal weeks associated with early postnatal blood gas derangements among infants born before the 28th week of gestation. The ELGAN Study 
Cytokine  2011;56(2):392-398.
Aim
To explore the relationships between blood gas derangements and blood concentrations of inflammation-related proteins shortly after preterm birth.
Design
Observational cohort
Setting
14 neonatal intensive care units
Subjects
734 infants born before the 28th week of gestation who were classified by their blood gas derangements during the first three postnatal days and by the concentrations of 25 proteins in their blood on days 1, 7, and 14. We classified these newborns by whether or not they had a highest or lowest PaO2, PCO2, and lowest pH in the most extreme quartile, and by whether or not they had a protein concentration in the highest quartile.
Results
Blood gas derangements on two days were much more likely to be accompanied or followed by sustained or recurrent systemic inflammation than a derangement on only one day. This was most evident for acidemia, and slightly less so for hypercapnia.
Conclusions
Our finding that protein concentration patterns indicative of systemic inflammation are associated with several blood gas derangements raises the possibility that organ damage attributed to these derangements might be accompanied by or involve an inflammatory response.
doi:10.1016/j.cyto.2011.07.014
PMCID: PMC4747654  PMID: 21821429
preterm infant; blood; cytokine; inflammation; acidemia; hypercapnia
20.  Proficient Motor Impulse Control in Parkinson Disease patients with Impulsive and Compulsive Behaviors 
Background
Parkinson Disease (PD) patients treated with Dopamine Agonist therapy can develop maladaptive reward-driven behaviors, known as Impulse Control Disorder (ICD). In this study, we assessed if ICD patients have evidence of motor-impulsivity.
Methods
We used the stop-signal task in a cohort of patients with and without active symptoms of ICD to evaluate motor-impulsivity. Of those with PD, 12 were diagnosed with ICD symptoms (PD-ICD) and were assessed before clinical reduction of Dopamine Agonist medication; 12 were without symptoms of ICD [PD-control] and taking equivalent dosages of Dopamine Agonist. Levodopa, if present, was maintained in both settings. Groups were similar in age, duration, and severity of motor symptoms, levodopa co-therapy, and total levodopa daily dose. All were tested in the Dopamine Agonist medicated and acutely withdrawn (24 hours) state, in a counterbalanced manner. Primary outcome measures were mean reaction time to correct go trials (Go Reaction Time), and mean stop-signal reaction time (SSRT).
Results
ICD patients produce faster SSRT than both Healthy Controls, and PD Controls. Faster SSRT in ICD patients is apparent in both Dopamine Agonist medication states. Also, we show unique dopamine medication effects on GoRT. In Dopamine Agonist monotherapy patients, Dopamine Agonist administration speeds Go Reaction Time. Conversely, in those with levodopa co-therapy, Dopamine Agonist administration slows Go Reaction Time.
Discussion
PD patients with active ICD symptoms are significantly faster at stopping initiated motor actions, and this is not altered by acute Dopamine Agonist withdrawal. In addition, the effect of Dopamine Agonist on Go Reaction Time is strongly influenced by the presence or absence of levodopa, even though levodopa co-therapy does not appear to influence SSRT. We discuss these findings as they pertain to the multifaceted definition of ‘impulsivity,’ the lack of evidence for motor-impulsivity in PD-ICD, and dopamine effects on motor-control in PD.
doi:10.1016/j.pbb.2014.11.017
PMCID: PMC4300241  PMID: 25459105
Dopamine Agonist; Parkinson Disease; Impulse Control Disorder; Inhibition; Motor impulsivity; Reaction Time
21.  Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes 
British Journal of Pharmacology  2014;172(3):721-736.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.
doi:10.1111/bph.12943
PMCID: PMC4301685  PMID: 25231355
23.  Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder 
British Journal of Pharmacology  2014;172(2):571-582.
BACKGROUND AND PURPOSE
Single-prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), also induces long-lasting hyperalgesia associated with hypocortisolism and elevated nociceptin/orphanin FQ (N/OFQ) levels in serum and CSF. Here, we determined the effect of JTC-801 (N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride), a nociceptin/orphanin FQ peptide (NOP) receptor antagonist, on symptoms of pain and anxiety in rats after SPS exposure, and examined N/OFQ-NOP receptor system changes.
EXPERIMENTAL APPROACH
Male Sprague Dawley rats received JTC-801 (6 mg kg−1 i.p., once daily) during days 7–21 of SPS. The ability of JTC-801 to inhibit N/OFQ-stimulated [35S]-GTPγS binding was confirmed in rat brain membranes. Anxiety-like behaviour and pain sensitivity were monitored by changes in elevated plus maze performance and withdrawal responses to thermal and mechanical stimuli. Serum corticosterone and N/OFQ content in CSF, serum and brain tissues were determined by radioimmunoassay; NOP receptor protein and gene expression in amygdala, hippocampus and periaqueductal grey (PAG) were examined by immunoblotting and real-time PCR respectively.
KEY RESULTS
JTC-801 treatment reversed SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. Elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS were blocked by JTC-801; daily JTC-801 treatment also reversed NOP receptor protein and mRNA up-regulation in amygdala and PAG.
CONCLUSION AND IMPLICATIONS
JTC-801 reversed SPS-induced anxiety- and pain-like behaviours, and NOP receptor system up-regulation. These findings suggest that N/OFQ plays an important role in hyperalgesia and allodynia maintenance after SPS. NOP receptor antagonists may provide effective treatment for co-morbid PTSD and pain.
LINKED ARTICLES
This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
doi:10.1111/bph.12701
PMCID: PMC4292969  PMID: 24666365
PTSD; elevated plus maze; pain sensitivity; nociceptin/orphanin FQ; nociceptin/orphanin FQ peptide receptor; single-prolonged stress; hypocortisolism; allodynia; JTC-801; von Frey test
24.  Elena Gracheva: Ion channels run hot and cold 
The Journal of Cell Biology  2015;209(6):778-779.
Gracheva studies the molecular basis and evolutionary origins of hibernation.
Gracheva studies the molecular basis and evolutionary origins of hibernation.
doi:10.1083/jcb.2096pi
PMCID: PMC4477860  PMID: 26101213
25.  Logic regression-derived algorithms for syndromic management of vaginal infections 
Background
Syndromic management of vaginal infections is known to have poor diagnostic accuracy. Logic regression is a machine-learning procedure which allows for the identification of combinations of variables to predict an outcome, such as the presence of a vaginal infection.
Methods
We used logic regression to develop predictive models for syndromic management of vaginal infection among symptomatic, reproductive-age women in south India. We assessed the positive predictive values, negative predictive values, sensitivities and specificities of the logic regression procedure and a standard WHO algorithm against laboratory-confirmed diagnoses of two conditions: metronidazole-sensitive vaginitis [bacterial vaginosis or trichomoniasis (BV/TV)], and vulvovaginal candidiasis (VVC).
Results
The logic regression procedure created algorithms which had a mean positive predictive value of 61 % and negative predictive value of 80 % for management of BV/TV, and a mean positive predictive value of 26 % and negative predictive value of 98 % for management of VVC. The results using the WHO algorithm were similarly mixed.
Conclusions
The logic regression procedure identified the most predictive measures for management of vaginal infections from the candidate clinical and laboratory measures. However, the procedure provided further evidence as to the limits of syndromic management for vaginal infections using currently available clinical measures.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-015-0228-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s12911-015-0228-5
PMCID: PMC4681120  PMID: 26674351
Sensitivity and specificity; India; Vaginitis; Epidemiologic methods; Humans; Female; Regression analysis; Algorithms

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