Miracle-dz/UniFAR-FTUs huggingface dataset:
Cognitive Impairment Following Acute Mild Traumatic Brain Injury

Patients with mild traumatic brain injury (mTBI) may present cognitive deficits within the first 24 h after trauma, herein called “acute phase,” which in turn may lead to long-term functional impairment and decrease in quality of life. Few studies investigated cognition in mTBI patients during the acute phase. The objectives of this study were to investigate the cognitive profile of patients with mTBI during the acute phase, compared to controls and normative data, and whether loss of consciousness (LOC), previous TBI and level of education influence cognition at this stage. Fifty-three patients with mTBI (aged 19–64 years) and 28 healthy controls participated in the study. All patients were evaluated at bedside within 24 h post-injury. Demographic and clinical data were registered. Cognitive function was assessed with the Mini-mental state examination (MMSE), the Frontal Assessment Battery (FAB), Digit Span (working memory), and the Visual Memory Test/Brief Cognitive Battery (for episodic memory). The clinical sample was composed mainly by men (58.5%). The mean age was 39 years-old and 64.3% of the patients had more than 8 years of education. The most common causes of mTBI were fall from own height (28.3%), aggression (24.5%), and fall from variable heights (24.5%). Compared to controls, mTBI patients exhibited significantly worse performance on MMSE, FAB, naming, incidental memory, immediate memory, learning, and delayed recall. Compared to normative data, 26.4% of patients had reduced global cognition as measured by the MMSE. Episodic memory impairment (13.2%) was more frequent than executive dysfunction (9.4%). No significant differences were found in cognitive performance when comparing patients with or without LOC or those with or without history of previous TBI. Patients with lower educational level had higher rates of cognitive impairment (VMT naming−28.6 vs. 4.2%; VMT immediate memory−32 vs. 4.2%; VMT learning−39.3 vs. 4.2%, all p < 0.05). In sum, we found significant cognitive impairment in the acute phase of mTBI, which was not associated with LOC or history of TBI, but appeared more frequently in patients with lower educational level.
Isolation and identification of new inner membrane‐associated proteins that localize to cell poles in Escherichia coli

Several bacterial structures, processes and proteins are localized primarily to the poles of rod‐shaped cells. To better understand this cellular organization, we devised a new method for identifying proteins that localize to the poles of Escherichia coli. Pole‐derived membrane fragments were isolated by affinity capture of vesicles containing the chemotaxis protein, Tar; and for comparison, vesicles representing all parts of the cytoplasmic membrane were captured by expressing a Tar variant that was no longer pole‐specific. A combination of one‐dimensional SDS‐PAGE and semi‐quantitative mass spectrometry identified 31 proteins that were highly enriched in polar vesicles. Five were chemotaxis proteins known to be pole‐specific and another, Aer, was an aerotaxis protein that had not yet been localized to the pole. The behaviour of these internal controls validated the overall approach. GFP‐fused derivatives of four candidates (Aer, YqjD, TnaA and GroES) formed polar foci that were distinct from inclusion bodies. TnaA–GFP and GroES–GFP were functional, formed a single focus per cell, and competed for polar localization with the wild‐type versions of these proteins. Polar localization of TnaA, GroES and YqjD was disrupted in cells lacking the MinCDE proteins, suggesting that this system may help localize proteins not involved in cell division.
Role of mitofusin 2 (Mfn2) in controlling cellular proliferation

It has been reported that Mitofusin2 (Mfn2) inhibits cell proliferation when overexpressed. We wanted to study the role of endogenous Mfn2 in cell proliferation, along with the structural features of Mfn2 that influence its mitochondrial localization and control of cell proliferation. Mfn2‐knockdown clones of a B‐cell lymphoma cell line BJAB exhibited an increased rate of cell proliferation. A 2‐fold increase in cell proliferation was also observed in Mfn2‐knockout mouse embryonic fibroblast (MEF) cells as compared with the control wild‐type cells, and the proliferative advantage of the knockout MEF cells was blocked on reintroduction of the Mfn2 gene. Mfn2 exerts its antiproliferative effect by acting as an effector molecule of Ras, resulting in the inhibition of the Ras‐Raf‐ERK signaling pathway. Furthermore, both the N‐terminal (aa 1–264) and the C‐terminal (aa 265–757) fragments of Mfn2 blocked cell proliferation through distinct mechanisms: the N‐terminal‐mediated inhibition was due to its interaction with Raf‐1, whereas the C‐terminal fragment of Mfn2 inhibited cell proliferation by interacting with Ras. The inhibition of proliferation by the N‐terminal fragment was independent of its mitochondrial localization. Collectively, our data provide new insights regarding the role of Mfn2 in controlling cellular proliferation. —Chen, K. ‐H. , Dasgupta, A. , Ding, J., Indig, F. E. , Ghosh, P., Longo, D. L. Role of Mitofusin 2 (Mfn2) in controlling cellular proliferation. FASEB J. 28, 382–394 (2014). www.fasebj. org
Exchange protein activated by cAMP 1 (Epac1)‐deficient mice develop β‐cell dysfunction and metabolic syndrome

Previously, exchange protein directly activated by cAMP 2 (Epac2) and PKA were known to play a role in glucose‐stimulated insulin secretion (GSIS) by pancreatic β cells. The present study shows that Epac1 mRNA is also expressed by β cells. Therefore, we generated mice and embryonic stem (ES) cells with deletion of the Epac1 gene to define its role in β‐cell biology and metabolism. The homozygous Epac1‐ knockout (Epac1–/–) mice developed impaired glucose tolerance and GSIS with deranged islet cytoarchitecture, which was confirmed by isolated islets from adult Epac1–/– mice. Moreover, Epac1–/– mice developed more severe hyperglycemia with increased β‐cell apoptosis and insulitis after multiple low‐dose streptozotocin (MLDS; 40 mg/kg) treatment than Epac1+/+ mice. Interestingly, Epac1–/– mice also showed metabolic defects, including increased respiratory exchange ratio (RER) and plasma triglyceride (TG), and more severe diet‐induced obesity with insulin resistance, which may contributed to β‐cell dysfunction. However, islets differentiated from Epac1–/– ES cells showed insulin secretion defect, reduced Glut2 and PDX‐1 expression, and abolished GLP‐1‐stimulated PCNA induction, suggesting a role of Epac1 in β‐cell function. The current study provides in vitro and in vivo evidence that Epac1 has an important role in GSIS of β cells and phenotype resembling metabolic syndrome. Kai, A. K. L. , Lam, A. K. M. , Chen, Y. , Tai, A. C. P., Zhang, X. , Lai, A. K. W. , Yeung, P. K. K. , Tam, S. , Wang, J., Lam, K. S. , Vanhoutte, P. M. , Bos, J. L. , Chung, S. S. M. , Xu, A. , Chung, S. K. Exchange protein activated by cAMP 1 (Epac1)‐deficient mice develop β‐cell dysfunction and metabolic syndrome. FASEBJ. 27, 4122–4135 (2013). www.fasebj. org
A Carboxyl-terminal Sequence in the Lutropin β Subunit Contributes to the Sorting of Lutropin to the Regulated Pathway*

Although synthesized in the same pituitary gonadotropes, the secretion profiles of lutropin (LH) and follitropin (FSH) differ. LH is secreted through a regulated pathway and associated with a bolus release at mid-estrous cycle. In contrast, the majority of FSH is secreted constitutively with an incremental increase until ovulation. Both share an identicalα subunit, and thus theβ subunit contains determinants for sorting into the regulated pathway. Previously, we demonstrated that a hydrophobic carboxyl-terminal heptapeptide of the LHβ subunit (Leu-Ser-Gly-Leu-Leu-Phe-Leu), not found in the FSHβ subunit, influences the intracellular behavior of the LH dimer. To test the hypothesis that the peptide contributes to differential sorting, we monitored the fates of LH and LHΔT (LHβ subunit lacking the carboxyl-terminal seven amino acids) dimers in the rat somatotrope-derived GH3 cell line in which both the regulated and constitutive secretory pathways operate. Pulse-chase labeling demonstrated that the LHΔT dimer was diverted to the constitutive pathway, resulting in a significant decrease in the corresponding intracellular pool. Forskolin stimulated LH dimer release 3-fold, which was accompanied by a parallel decrease of intracellular LH; only marginal forskolin stimulation of LHΔT was seen. Immunofluorescence after cycloheximide treatment demonstrated decreased retention of LHΔT compared with LH, consistent with increased constitutive secretion of LHΔT. We also demonstrated that fusing the heptapeptide to the carboxyl terminus of the FSHβ subunit resulted in an increased regulated secretion of this FSH analog compared with wild-type FSH. These data are the first to identify a novel structural determinant responsible for the sorting of a member of the glycoprotein hormone family into the regulated secretory pathway.
Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1‐BMAL1 pathway

Patients with obstructive lung diseases display abnormal circadian rhythms in lung function. We determined the mechanism whereby environmental tobacco/cigarette smoke (CS) modulates expression of the core clock gene BMAL1, through Sirtuin1 (SIRT1) deacetylase during lung inflammatory and injurious responses. Adult C57BL6/J and various mice mutant for SIRT1 and BMAL1 were exposed to both chronic (6 mo) and acute (3 and 10 d) CS, and we measured the rhythmic expression of clock genes, circadian rhythms of locomotor activity, lung function, and inflammatory and emphysematous responses in the lungs. CS exposure (100–300 mg/m3 particulates) altered clock gene expression and reduced locomotor activity by disrupting the central and peripheral clocks and increased lung inflammation, causing emphysema in mice. BMAL1 was acetylated and degraded in the lungs of mice exposed to CS and in patients with chronic obstructive pulmonary disease (COPD), compared with lungs of the nonsmoking controls, linking it mechanistically to CS‐induced reduction of SIRT1. Targeted deletion of Bmal1 in lung epithelium augmented inflammation in response to CS, which was not attenuated by the selective SIRT1 activator SRT1720 (EC50=0.16 μM) in these mice. Thus, the circadian clock, specifically the enhancer BMAL1 in epithelium, plays a pivotal role, mediated by SIRT1‐dependent BMAL1, in the regulation of CS‐induced lung inflammatory and injurious responses. —Hwang, J.‐W. , Sundar, I. K. , Yao, H. , Sellix, M. T. , Rahman, I. Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1‐BMAL1 pathway. FASEB J. 28, 176–194 (2014). www.fasebj. org
Mechanism of the asymmetric activation of the MinD ATPase by MinE

MinD is a component of the Min system involved in the spatial regulation of cell division. It is an ATPase in the MinD/ParA/Mrp deviant Walker A motif family which is within the P loop GTPase superfamily. Its ATPase activity is stimulated by MinE; however, the mechanism of this activation is unclear. MinD forms a symmetric dimer with two binding sites for MinE; however, a recent model suggested that MinE occupying one site was sufficient for ATP hydrolysis. By generating heterodimers with one binding site for MinE we show that one binding site is sufficient for stimulation of the MinD ATPase. Furthermore, comparison of structures of MinD and related proteins led us to examine the role of N45 in the switch I region. An asparagine at this position is conserved in four of the deviant Walker A motif subfamilies (MinD, chromosomal ParAs, Get3 and FleN) and we find that N45 in MinD is essential for MinE‐stimulated ATPase activity and suggest that it is a key residue affected by MinE binding.
Decreased long‐chain fatty acid oxidation impairs postischemic recovery of the insulin‐resistant rat heart

Diabetic patients with acute myocardial infarction are more likely to die than nondiabetic patients. In the present study we examined the effect of insulin resistance on myocardial ischemia tolerance. Hearts of rats, rendered insulin resistant by high‐sucrose feeding, were subjected to ischemia/reperfusion ex vivo. Cardiac power of control hearts from chow‐fed rats recovered to 93%, while insulin‐resistant hearts recovered only to 80% (P< 0.001 vs. control). Unexpectedly, impaired contractile recovery did not result from an impairment of glucose oxidation (576±36 vs. 593±42 nmol/min/g dry weight; not significant), but from a failure to increase and to sustain oxidation of the long‐chain fatty acid oleate on reperfusion (1878±56 vs. 2070±67 nmol/min/g dry weight; P<0.05). This phenomenon was due to a reduced ability to transport oleate into mitochondria and associated with a 38–58% decrease in the mitochondrial uncoupling protein 3 (UCP3) levels. Contractile function was rescued by replacing oleate with a medium‐chain fatty acid or by restoring UCP3 levels with 24 h of food withdrawal. Lastly, the knockdown of UCP3 in rat L6 myocytes also decreased oleate oxidation by 13–18% following ischemia. Together the results expose UCP3 as a critical regulator of long‐chain fatty acid oxidation in the stressed heart postischemia and identify octanoate as an intervention by which myocardial metabolism can be manipulated to improve function of the insulin‐resistant heart. —Harmancey, R. , Vasquez, H. G. , Guthrie, P. H. , Taegtmeyer, H. , Decreased long‐chain fatty acid oxidation impairs postischemic recovery of the insulin‐resistant rat heart. FASEB J. 27, 3966–3978 (2013). www.fasebj. org
Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5)

Interstitial lung diseases (ILDs) are characterized by injury, inflammation, and scarring of alveoli, leading to impaired function. The etiology of idiopathic forms of ILD is not understood, making them particularly difficult to study due to the lack of appropriate animal models. Consequently, few effective therapies have emerged. We developed an inbred mouse model of ILD using vanadium pentoxide (V2O5), the most common form of a transition metal found in cigarette smoke, fuel ash, mineral ores, and steel alloys. Pulmonary responses to V2O5, including dose‐dependent increases in lung permeability, inflammation, collagen content, and dysfunction, were significantly greater in DBA/2J mice compared to C57BL/6J mice. Inflammatory and fibrotic responses persisted for 4 mo in DBA/2J mice, while limited responses in C57BL/6J mice resolved. We investigated the genetic basis for differential responses through genetic mapping of V2O5‐induced lung collagen content in BXD recombinant inbred (RI) strains and identified significant linkage on chromosome 4 with candidate genes that associate with V2O5‐induced collagen content across the RI strains. Results suggest that V2O5 may induce pulmonary fibrosis through mechanisms distinct from those in other models of pulmonary fibrosis. These findings should further advance our understanding of mechanisms involved in ILD and thereby aid in identification of new therapeutic targets. —Walters, D. M. , White, K. M. , Patel, U. , Davis, M. J., Veluci‐Marlow, R. M. , Bhupanapadu Sunkesula, S. R. , Bonner, J. C. , Martin, J. R. , Gladwell, W. , Kleeberger, S. R. Genetic susceptibility to interstitial pulmonary fibrosis in mice induced by vanadium pentoxide (V2O5). FASEB J. 28, 1098–1112 (2014). www.fasebj. org
Immunodeficiency and Immunomonitoring

Abstract Immunological diagnostics is a rapidly developing area in laboratory medicine. Most recently, major developments in the area of immunodeficiency and the monitoring of chronic inflammatory diseases have been observed. Regarding immuno-monitoring, recently a consensus panel for basic flow cytometry has been published together with age-related reference values. In the USA, the search for severe inherited immunodeficiency diseases (such as severe combined immunodeficiency disease, SCID) is part of neonatal screening procedures. Recently, several US states published first results which are based on the measurement of T-cell receptor excision circles (TRECs). Furthermore, age-dependent reference values for the measurement of IgG subclasses and subclass-specific vaccination antibodies have been published. Monitoring of chronic inflammatory disease focuses on asthma. A novel classification based on the cellular distribution of neutrophils versus eosinophils in induced sputum has been developed. Furthermore, novel biomarkers, such as periostin, are currently under evaluation. Such novel approaches of phenotyping are now the basis of individualized therapeutic approaches in patients with (severe) asthma, who respond to certain biologicals.
Stochasticity of TOL plasmid catabolic promoters sets a bimodal expression regime in Pseudomonas putida mt‐2 exposed to m‐xylene

The expression dynamics of the catabolic promoters of the TOL plasmid pWW0 has been examined in single cells of Pseudomonas putida mt‐2 exposed to m‐xylene. To this end, we employed an á la carte bi‐cistronic gfp–lacZ reporter system for generating monocopy transcriptional fusions to each of the four promoters (Pr, Ps, Pu and Pm) of the regulatory network. Whereas expression of xylR (the master regulatory gene of the TOL system) behaved in a unimodal fashion, the activation of Pu and Pm displayed a high degree of stochasticity. This event resulted in a time‐dependent shift in the bacterial population between two induction states without intermediate expression levels. Bimodality of the Pm promoter for the lower TOL pathway was largely due to the propagation of the Ps output throughout the network, which caused stochastic overproduction of the second regulator of the system, XylS. Surprisingly, activation of Pm by the form of XylS that was bound to the pathway intermediate 3‐methylbenzoate was relatively minor. These stochastic phenomena in response to m‐xylene disappeared in the stationary phase. Taken together, the data suggests that genetically homogeneous populations of P. putida mt‐2 employ a strategy of phenotypic variation (metabolic bet‐hedging) when confronted with mixtures of nutrients.
Managing corneal ectasia prior to keratoplasty

The advent of refractive surgery allowed for great advances in the understanding of pathophysiology, diagnosis and treatment of corneal ectatic diseases. The different associations that highlight the importance of this range from the need for early diagnosis in the screening process of candidates for laser vision correction to the impact of refractive surgery technologies on treatment. Keratoconus is still an indication for corneal transplant, and it is expected that about 5–20% of the patients may require it. However, considering technological advances, the current treatment options are diverse and can be customized to each case. This review overviews the fundamental knowledge related to corneal ectatic diseases management and its management prior to keratoplasty. Whereas this is an area of dynamic development of scientific knowledge, we present fundamental concepts, along with information on the most recent studies and future prospects.
Evaluation of therapeutic effects of natural killer (NK) cell‐based immunotherapy in mice using in vivo apoptosis bioimaging with a caspase‐3 sensor

Natural killer (NK) cell‐based immunotherapy is a promising strategy for cancer treatment, and caspase‐3 is an important effector molecule in NK cell‐mediated apoptosis in cancers. Here, we evaluated the antitumor effects of NK cell‐based immunotherapy by serial noninvasive imaging of apoptosis using a caspase‐3 sensor in mice with human glioma xenografts. Human glioma cells expressing both a caspase‐3 sensor as a surrogate marker for caspase‐3 activation and Renilla luciferase (Rluc) as a surrogate marker for cell viability were established and referred to as D54‐CR cells. Human NK92 cells were used as effector cells. Treatment with NK92 cells resulted in a time‐ and effector number‐dependent increase in bioluminescence imaging (BLI) activity of the caspase‐3 sensor in D54‐CR cells in vitro. Caspase‐3 activation by NK92 treatment was blocked by Z‐VAD treatment in D54‐CR cells. Transfusion of NK92 cells induced an increase of the BLI signal by caspase‐3 activation in a dose‐ and time‐dependent manner in D54‐CR tumor‐bearing mice but not in PBS‐treated mice. Accordingly, sequential BLI with the Rluc reporter gene revealed marked retardation of tumor growth in the NK92‐treatment group but not in the PBS‐treatment group. These data suggest that noninvasive imaging of apoptosis with a caspase‐3 sensor can be used as an effective tool for evaluation of therapeutic efficacy as well as for optimization of NK cell‐based immunotherapy. —Lee, H. W. , Singh, T. D. , Lee, S. ‐W. , Ha, J.‐H. , Rehemtulla, A. , Ahn, B. ‐C. , Jeon, Y. ‐H. , Lee, J. Evaluation of therapeutic effects of natural killer (NK) cell‐based immunotherapy in mice using in vivo apoptosis bioimaging with a caspase‐3 sensor. FASEB J. 28, 2932–2941 (2014). www.fasebj. org
The Role of Wrap Around Services in Retention and Outcome in Substance Abuse Treatment: Findings From the Wrap Around Services Impact Study

ObjectivesSubstance abuse, a multidimensional disorder, is frequently complicated by additional psychosocial needs that, left unresolved, may adversely affect clients' treatment retention and outcome. This article presents and discusses findings of a study designed to identify associations between specific wrap around services and indicators of treatment retention and posttreatment outcome. MethodsUsing data gathered in the Wrap Around Services Impact Study (WASIS) funded by the Center for Substance Abuse Treatment (CSAT), we analyzed the contribution of wrap around service receipt to multiple indicators of retention and outcome. ResultsResults of these analyses indicated a strong association between medical, educational, and mental health services and several indicators of retention. Receipt of basic needs, child care, educational, family, and medical services was associated with improvements in several posttreatment outcomes. Analyses also indicated a significant moderating role of site characteristics (i.e., program treatment individualization and intensity; program emphasis on facilitating receipt of wrap around services) on outcomes associated with wrap around service receipt. ConclusionsThe clinical implications of these findings support policies that address clients' broader biopsychosocial needs while substance abuse treatment is provided.