bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural Basis of Type 2 Secretion System Engagement between the Inner and Outer Bacterial Membranes
Authors: Hay Iain D. , Belousoff Matthew J. , Lithgow Trevor 
Published: October 2017

ABSTRACT

Sophisticated nanomachines are used by bacteria for protein secretion. In Gram-negative bacteria, the type 2 secretion system (T2SS) is composed of a pseudopilus assembly platform in the inner membrane and a secretin complex in the outer membrane. The engagement of these two megadalton-sized complexes is required in order to secrete toxins, effectors, and hydrolytic enzymes.
Pseudomonas aeruginosa
has at least two T2SSs, with the ancestral nanomachine having a secretin complex composed of XcpQ. Until now, no high-resolution structural information was available to distinguish the features of this
Pseudomonas
-type secretin, which varies greatly in sequence from the well-characterized
Klebsiella
-type and
Vibrio
-type secretins. We have purified the ~1-MDa secretin complex and analyzed it by cryo-electron microscopy. Structural comparisons with the
Klebsiella
-type secretin complex revealed a striking structural homology despite the differences in their sequence characteristics. At 3.6-Å resolution, the secretin complex was found to have 15-fold symmetry throughout the membrane-embedded region and through most of the domains in the periplasm. However, the N1 domain and N0 domain were not well ordered into this 15-fold symmetry. We suggest a model wherein this disordering of the subunit symmetry for the periplasmic N domains provides a means to engage with the 6-fold symmetry in the inner membrane platform, with a metastable engagement that can be disrupted by substrate proteins binding to the region between XcpP, in the assembly platform, and the XcpQ secretin.

IMPORTANCE
How the outer membrane and inner membrane components of the T2SS engage each other and yet can allow for substrate uptake into the secretin chamber has challenged the protein transport field for some time. This vexing question is of significance because the T2SS collects folded protein substrates in the periplasm for transport out of the bacterium and yet must discriminate these few substrate proteins from all the other hundred or so folded proteins in the periplasm. The structural analysis here supports a model wherein substrates must compete against a metastable interaction between XcpP in the assembly platform and the XcpQ secretin, wherein only structurally encoded features in the T2SS substrates compete well enough to disrupt XcpQ-XcpP for entry into the XcpQ chamber, for secretion across the outer membrane.
Lipopolysaccharide from Crypt-Specific Core Microbiota Modulates the Colonic Epithelial Proliferation-to-Differentiation Balance
Authors: Naito Tomoaki , Mulet Céline , De Castro Cristina , Molinaro Antonio , Saffarian Azadeh , Nigro Giulia , Bérard Marion , Clerc Mélanie , Pedersen Amy B. , Sansonetti Philippe J. , Pédron Thierry 
Published: October 2017

ABSTRACT

We identified a crypt-specific core microbiota (CSCM) dominated by strictly aerobic, nonfermentative bacteria in murine cecal and proximal colonic (PC) crypts and hypothesized that, among its possible functions, it may affect epithelial regeneration. In the present work, we isolated representative CSCM strains using selective media based upon our initial 16S rRNA-based molecular identification (i.e.,
Acinetobacter
,
Delftia
, and
Stenotrophomonas
). Their tropism for the crypt was confirmed, and their influence on epithelial regeneration was demonstrated
in vivo
by monocolonization of germfree mice. We also showed that lipopolysaccharide (LPS), through its endotoxin activity, was the dominant bacterial agonist controlling proliferation. The relevant molecular mechanisms were analyzed using colonic crypt-derived organoids exposed to bacterial sonicates or highly purified LPS as agonists. We identified a Toll-like receptor 4 (TLR4)-dependent program affecting crypts at different stages of epithelial differentiation. LPS played a dual role: it repressed cell proliferation through RIPK3-mediated necroptosis of stem cells and cells of the transit-amplifying compartment and concurrently enhanced cell differentiation, particularly the goblet cell lineage.

IMPORTANCE
The LPS from crypt-specific core microbiota controls intestinal epithelium proliferation through necroptosis of stem cells and enhances cell differentiation, mainly the goblet cell lineage.
Can favourable psychosocial working conditions in midlife moderate the risk of work exit for chronically ill workers? A 20-year follow-up of the Whitehall II study
Authors: Fleischmann Maria , Carr Ewan , Stansfeld Stephen A , Xue Baowen , Head Jenny 
Published: October 2017

ObjectivesTo investigate if favourable psychosocial working conditions can reduce the risk of work exit and specifically for workers with chronic disease.MethodsMen and women (32%) aged 35–55, working and having no chronic disease at baseline of the Whitehall II study of London-based civil servants were selected (n=9040). We observed participants’ exit from work through retirement, health-related exit and unemployment, new diagnosis of chronic disease (ie, coronary heart disease, diabetes, stroke and cancer) and their psychosocial working conditions in midlife. Using cause-specific Cox models, we examined the association of chronic disease and favourable psychosocial working conditions and their interaction, with the three types of work exit. We adjusted for gender, occupational grade, educational level, remaining in civil service, spouse’s employment status and mental health.ResultsChronic disease significantly increased the risk of any type of work exit (HR 1.27) and specifically the risk of health-related exit (HR 2.42). High skill discretion in midlife reduced the risk of any type of work exit (HR 0.90), retirement (HR 0.91) and health-related exit (HR 0.68). High work social support in midlife decreased the risk of health-related exit (HR 0.79) and unemployment (HR 0.71). Favourable psychosocial working conditions in midlife did not attenuate the association between chronic disease and work exit significantly.ConclusionsThe chronically ill have increased risks of work exit, especially through health-related exit routes. Chronic disease is an obstacle to extended working lives. Favourable working conditions directly relate to reduced risks of work exit.
Paired corticospinal-motoneuronal stimulation increases maximal voluntary activation of human adductor pollicis
Authors: D’Amico Jessica M. , Dongés Siobhan C. , Taylor Janet L. 
Published: October 2017

Paired corticospinal-motoneuronal stimulation (PCMS), which delivers repeated pairs of transcranial magnetic stimuli (TMS) and maximal motor nerve stimuli, can alter corticospinal transmission to low-threshold motoneurons in the human spinal cord. To determine whether similar changes occur for high-threshold motoneurons, we tested whether maximal voluntary activation and force can be affected by PCMS in healthy individuals. On 2 separate days, healthy participants ( n = 14) performed brief thumb adduction maximal voluntary contractions (MVCs) before and after a control protocol (TMS only) or PCMS designed to facilitate corticospinal transmission to adductor pollicis. Peripheral nerve stimulation alone was not performed. During each MVC, a superimposed twitch was elicited by a supramaximal stimulus delivered to the ulnar nerve. With muscles relaxed following the maximal contraction, a similar stimulus elicited a resting twitch. Voluntary activation was calculated as (1 − superimposed twitch/resting twitch) × 100%. Although voluntary activation decreased over time in both conditions, the decrease was less after PCMS (−0.4 ± 4.1%) than after the control protocol (−4.9 ± 4.9%; P = 0.007). This was supported by a greater increase in electromyographic response after PCMS than control (7 ± 13% vs. −3 ± 10%; P = 0.043). However, maximal force was not affected. The findings indicate a modest effect of PCMS on maximal neural drive to adductor pollicis, suggesting that PCMS can affect corticospinal transmission to high-threshold motoneurons. NEW & NOTEWORTHY Paired corticospinal-motoneuronal stimulation (PCMS) induces changes in the human spinal cord. To date, the reported effects of PCMS have been limited to low-threshold motoneurons and low-force tasks in healthy and spinal cord injured individuals. For the first time, we show that these plastic changes are not limited to lower threshold motoneurons, but occur across the entire motoneuron pool as demonstrated by the increases in voluntary activation and muscle activity during maximal voluntary contractions of adductor pollicis.
Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation
Authors: Bell Jonathan B. , Eckerdt Frank , Dhruv Harshil D. , Finlay Darren , Peng Sen , Kim Seungchan , Kroczynska Barbara , Beauchamp Elspeth M. , Alley Kristen , Clymer Jessica , Goldman Stewart , Cheng Shi-Yuan , James C. David , Nakano Ichiro , Horbinski Craig , Mazar Andrew P. , Vuori Kristiina , Kumthekar Priya , Raizer Jeffrey , Berens Michael E. , Platanias Leonidas C. 
Published: October 2017

Abstract
Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood–brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1–eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival.
Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32–46. ©2017 AACR.
Influence of Contrast Media Dose and Osmolality on the Diagnostic Performance of Contrast Fractional Flow Reserve
Authors: Nishi Takeshi , Johnson Nils P. , De Bruyne Bernard , Berry Colin , Gould K. Lance , Jeremias Allen , Oldroyd Keith G. , Kobayashi Yuhei , Choi Dong-Hyun , Pijls Nico H.J. , Fearon William F. 
Published: October 2017

Background—
Contrast fractional flow reserve (cFFR) is a method for assessing functional significance of coronary stenoses, which is more accurate than resting indices and does not require adenosine. However, contrast media volume and osmolality may affect the degree of hyperemia and therefore diagnostic performance.

Methods and Results—

cFFR, instantaneous wave–free ratio, distal pressure/aortic pressure at rest, and FFR were measured in 763 patients from 12 centers. We compared the diagnostic performance of cFFR between patients receiving low or iso-osmolality contrast (n=574 versus 189) and low or high contrast volume (n=341 versus 422) using FFR≤0.80 as a reference standard. The sensitivity, specificity, and overall accuracy of cFFR for the low versus iso-osmolality groups were 73%, 93%, and 85% versus 87%, 90%, and 89%, and for the low versus high contrast volume groups were 69%, 99%, and 83% versus 82%, 93%, and 88%. By receiver operating characteristics (ROC) analysis, cFFR provided better diagnostic performance than resting indices regardless of contrast osmolality and volume (
P
<0.001 for all groups). There was no significant difference between the area under the curve of cFFR in the low- and iso-osmolality groups (0.938 versus 0.957;
P
=0.40) and in the low- and high-volume groups (0.939 versus 0.949;
P
=0.61). Multivariable logistic regression analysis showed that neither contrast osmolality nor volume affected the overall accuracy of cFFR; however, both affected the sensitivity and specificity.

Conclusions—
The overall accuracy of cFFR is greater than instantaneous wave–free ratio and distal pressure/aortic pressure and not significantly affected by contrast volume and osmolality. However, contrast volume and osmolality do affect the sensitivity and specificity of cFFR.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02184117.
Angiotensin II Receptor–Neprilysin Inhibitor Sacubitril/Valsartan Improves Endothelial Dysfunction in Spontaneously Hypertensive Rats
Authors: Seki Takunori , Goto Kenichi , Kansui Yasuo , Ohtsubo Toshio , Matsumura Kiyoshi , Kitazono Takanari 
Published: October 2017

Background

We have previously demonstrated that antihypertensive treatment with renin‐angiotensin system inhibitors restores the impaired endothelium‐dependent hyperpolarization (
EDH
)–mediated responses in spontaneously hypertensive rats (
SHR
s). Herein, we investigated whether the angiotensin
II
receptor–neprilysin inhibitor sacubitril/valsartan (
LCZ
696) would improve reduced
EDH
‐mediated responses and whether
LCZ
696 would exert additional effects on endothelium‐dependent and endothelium‐independent vasorelaxation compared with an angiotensin
II
type 1 receptor blocker alone during hypertension.

Methods and Results

SHR
s were treated for 3 months with either
LCZ
696 or valsartan, from the age of 8 to 11 months. Age‐matched, untreated
SHR
s and Wistar‐Kyoto rats served as controls. Membrane potentials and contractile responses were recorded from the isolated superior mesenteric arteries. Acetylcholine‐induced,
EDH
‐mediated responses were impaired in untreated
SHR
s compared with Wistar‐Kyoto rats.
EDH
‐mediated responses were similarly improved in the
LCZ
696‐ and valsartan‐treated
SHR
s. No difference was observed in acetylcholine‐induced, nitric oxide‐mediated relaxations among the 4 groups. Endothelium‐independent relaxations in response to a nitric oxide donor, sodium nitroprusside, and those to levcromakalim, an
ATP
‐sensitive K
+
‐channel opener, were similar among the 4 groups; however, the sensitivities to levcromakalim were significantly higher in both
LCZ
696‐ and valsartan‐treated
SHR
s.

Conclusions

LCZ
696 appears to be as effective as valsartan in improving the impaired
EDH
‐mediated responses during hypertension.
LCZ
696 and valsartan exert similar beneficial effects on endothelium‐independent relaxation via enhanced sensitivity of the
ATP
‐sensitive K
+
channel. However, the dual blockade of renin‐angiotensin system and neutral endopeptidase with
LCZ
696 does not appear to provide additional benefit over valsartan alone on vasomotor function in mesenteric arteries of
SHR
s.
Validation of the Telephone Interview of Cognitive Status and Telephone Montreal Cognitive Assessment Against Detailed Cognitive Testing and Clinical Diagnosis of Mild Cognitive Impairment After Stroke
Authors: Zietemann Vera , Kopczak Anna , Müller Claudia , Wollenweber Frank Arne , Dichgans Martin 
Published: October 2017

Background and Purpose—
Assessment of cognitive status poststroke is recommended by guidelines but follow-up can often not be done in person. The Telephone Interview of Cognitive Status (TICS) and the Telephone Montreal Cognitive Assessment (T-MoCA) are considered useful screening instruments. Yet, evidence to define optimal cut-offs for mild cognitive impairment (MCI) after stroke is limited.

Methods—
We studied 105 patients enrolled in the prospective DEDEMAS study (Determinants of Dementia After Stroke; NCT01334749). Follow-up visits at 6, 12, 36, and 60 months included comprehensive neuropsychological testing and the Clinical Dementia Rating scale, both of which served as reference standards. The original TICS and T-MoCA were obtained in 2 separate telephone interviews each separated from the personal visits by 1 week (1 before and 1 after the visit) with the order of interviews (TICS versus T-MoCA) alternating between subjects. Area under the receiver-operating characteristic curves was determined.

Results—
Ninety-six patients completed both the face-to-face visits and the 2 interviews. Area under the receiver-operating characteristic curves ranged between 0.76 and 0.83 for TICS and between 0.73 and 0.94 for T-MoCA depending on MCI definition. For multidomain MCI defined by multiple-tests definition derived from comprehensive neuropsychological testing optimal sensitivities and specificities were achieved at cut-offs <36 (TICS) and <18 (T-MoCA). Validity was lower using single-test definition, and cut-offs were higher compared with multiple-test definitions. Using Clinical Dementia Rating as the reference, optimal cut-offs for MCI were <36 (TICS) and approximately 19 (T-MoCA).

Conclusions—
Both the TICS and T-MoCA are valid screening tools poststroke, particularly for multidomain MCI using multiple-test definition.
Remote Ischemic Conditioning May Improve Outcomes of Patients With Cerebral Small-Vessel Disease
Authors: Wang Yuan , Meng Ran , Song Haiqing , Liu Gang , Hua Yang , Cui Dehua , Zheng Lemin , Feng Wuwei , Liebeskind David S. , Fisher Marc , Ji Xunming 
Published: October 2017

Background and Purpose—
We aimed to evaluate the efficacy of remote ischemic conditioning (RIC) in patients with cerebral small-vessel disease.

Methods—
Thirty patients with cerebral small-vessel disease–related mild cognitive impairment were enrolled in this prospective, randomized controlled study for 1 year. Besides routine medical treatment, participants were randomized into the experimental group (n=14) undergoing 5 cycles consisting of ischemia followed by reperfusion for 5 minutes on both upper limbs twice daily for 1 year or the control group (n=16) who were treated with sham ischemia–reperfusion cycles. The primary outcome was the change of brain lesions, and secondary outcomes were changes of cognitive function, plasma biomarkers, and cerebral hemodynamic parameters both at baseline and at the end of 1-year follow-up.

Results—

Compared with pretreatment, the post-treatment white matter hyperintensities volume in the RIC group was significantly reduced (9.10±7.42 versus 6.46±6.05 cm
3
;
P
=0.020), whereas no significant difference was observed in the sham-RIC group (8.99±6.81 versus 8.07±6.56 cm
3
;
P
=0.085). The reduction of white matter hyperintensities volume in the RIC group was more substantial than that in sham group (−2.632 versus −0.935 cm
3
;
P
=0.049). No significant difference was found in the change of the number of lacunes between 2 groups (0 versus 0;
P
=0.694). A significant treatment difference at 1 year on visuospatial and executive ability was found between the 2 groups (0.639 versus 0.191;
P
=0.048). RIC showed greater effects compared with sham-RIC on plasma triglyceride (−0.433 versus 0.236 mmol/L;
P
=0.005), total cholesterol (−0.975 versus 0.134 mmol/L;
P
<0.001), low-density lipoprotein (−0.645 versus −0.029 mmol/L;
P
=0.034), and homocysteine (−4.737 versus −1.679 µmol/L;
P
=0.044). Changes of the pulsation indices of middle cerebral arteries from the baseline to 1 year were different between the 2 groups (right: −0.075 versus 0.043;
P
=0.030; left: −0.085 versus 0.043;
P
=0.010).

Conclusions—
RIC seems to be potentially effective in patients with cerebral small-vessel disease in slowing cognition decline and reducing white matter hyperintensities.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01658306.
Justice and the City: A Reading of Amos 3:9-15
Authors: Ben-Dov Jonathan 
Published: October 2017

Abstract
The article strives to understand the urban prophecies in the Book of Amos with a view to spatial and literary concepts. Amos 3:9-15 is a collection of short prophecies, with v. 12 serving as its linchpin. The imagery of vv. 9-11 is part of an urban tradition in biblical literature, which underscores the importance of justice and peace for the maintenance of the city. Verses 12 and 15 constitute one prophecy about Samaria, which intensifies the tension between the city and its surroundings by contrasting items from the urban scenery with a gruesome picture of the lion in prey. Vv. 13-14 constitute a Bethel prophecy, introduced in between the Samaria prophecies. The city is poetically defined by the unification of its surroundings (the wall) with the edifices at its heart. Several cruxes in the interpretation of Amos 3:9-15 are elucidated throughout the discussion.
A Mother’s Refrain: Judges 5:28-30 in Cultural Context
Authors: Baker Robin 
Published: October 2017

Abstract
The Song of Deborah’s unusual language and style, and the potency of its imagery combine to make it one of the most analysed and debated texts in the Hebrew Bible. Although many aspects of the Song have remained opaque, there is scholarly consensus that it was composed in approximately the form we have it in the period of the Judges. This consensus is largely founded on linguistic analysis of the text. This article approaches the Song from a different direction. It considers the cultural markers found in Judges 5:28-30 and analyses what they reveal about the Sitz im Leben of these verses.
Variability of the Antarctic Slope Current System in the Northwestern Weddell Sea
Authors: Azaneu Marina , Heywood Karen J. , Queste Bastien Y. , Thompson Andrew F. 
Published: October 2017

AbstractThe dense water outflow from the Antarctic continental shelf is closely associated with the strength and position of the Antarctic Slope Front. This study explores the short-term and spatial variability of the Antarctic Slope Front system and the mechanisms that regulate cross-slope exchange using highly temporally and spatially resolved measurements from three ocean gliders deployed in 2012. The 22 sections along the eastern Antarctic Peninsula and west of the South Orkney Islands are grouped regionally and composited by isobaths. There is consistency in the front position around the Powell Basin, varying mostly between the 500- and 800-m isobaths. In most of the study area the flow is bottom intensified. The along-slope transport of the Antarctic Slope Current (upper 1000 m) varies between 0.2 and 5.9 Sv (1 Sv ≡ 106 m3 s−1) and does not exhibit a regional pattern. The magnitude of the velocity field shows substantial variability, up to twice its mean value. Higher eddy kinetic energy (0.003 m2 s−2) is observed in sections with dense water, possibly because of baroclinic instabilities in the bottom layer. Distributions of potential vorticity show an increase toward the shelf along isopycnals and also in the dense water layer. Glider sections located west of the South Orkney Islands indicate a northward direction of the flow associated with the Weddell Front, which differs from previous estimates of the mean circulation. This study provides some of the first observational confirmation of the high-frequency variability associated with an active eddy field that has been suggested by recent numerical simulations in this region.