bluuebunny/crossref_metadata_2025 huggingface dataset:
Threshold position control of anticipation in humans: a possible role of corticospinal influences
Authors: Zhang Lei , Turpin Nicolas A. , Feldman Anatol G.
Published: May 2017

Key points

Sudden unloading of preloaded wrist muscles elicits motion to a new wrist position. Such motion is prevented if subjects unload muscles using the contralateral arm (self‐unloading).

Corticospinal influences originated from the primary motor cortex maintain tonic influences on motoneurons of wrist muscles before sudden unloading but modify these influences prior to the onset and until the end of self‐unloading.

Results are interpreted based on the previous finding that intentional actions are caused by central, particularly corticospinal, shifts in the spatial thresholds at which wrist motoneurons are activated, thus predetermining the attractor point at which the neuromuscular periphery achieves mechanical balance with environment forces.

By maintaining or shifting the thresholds, descending systems let body segments go to the equilibrium position in the respective unloading tasks without the pre‐programming of kinematics or muscle activation patterns.

The study advances the understanding of how motor actions in general, and anticipation in particular, are controlled.

The role of corticospinal (CS) pathways in anticipatory motor actions was evaluated using transcranial magnetic stimulation (TMS) of the primary motor cortex projecting to motoneurons (MNs) of wrist muscles. Preloaded wrist flexors were suddenly unloaded by the experimenter or by the subject using the other hand (self‐unloading). After sudden unloading, the wrist joint involuntarily flexed to a new position. In contrast, during self‐unloading the wrist remained almost motionless, implying that an anticipatory postural adjustment occurred. In the self‐unloading task, anticipation was manifested by a decrease in descending facilitation of pre‐activated flexor MNs starting ∼72 ms before changes in the background EMG activity. Descending facilitation of extensor MNs began to increase ∼61 ms later. Conversely, these influences remained unchanged before sudden unloading, implying the absence of anticipation. We also tested TMS responses during EMG silent periods produced by brief muscle shortening, transiently resulting in similar EMG levels before the onset and after the end of self‐unloading. We found reduced descending facilitation of flexor MNs after self‐unloading. To explain why the wrist excursion was minimized in self‐unloading due to these changes in descending influences, we relied on previous demonstrations that descending systems pre‐set the threshold positions of body segments at which muscles begin to be activated, thus predetermining the equilibrium point to which the system is attracted. Based on this notion, a more consistent explanation of the kinematic, EMG and descending patterns in the two types of unloading is proposed compared to the alternative notion of direct pre‐programming of kinematic and/or EMG patterns.
Training alters the distribution of perilipin proteins in muscle following acute free fatty acid exposure
Authors: Shepherd S. O. , Strauss J. A. , Wang Q. , Dube J. J. , Goodpaster B. , Mashek D. G. , Chow L. S.
Published: May 2017

Key points

The lipid droplet (LD)‐associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, although whether the abundance and association of the PLIN proteins with LDs is related to the diverse lipid storage in muscle between trained and sedentary individuals is unknown.

We show that lipid infusion augments IMTG content in type I fibres of both trained and sedentary individuals. Most importantly, despite there being no change in PLIN protein content, lipid infusion did increase the number of LDs connected with PLIN proteins in trained individuals only.

We conclude that trained individuals are able to redistribute the pre‐existing pool of PLIN proteins to an expanded LD pool during lipid infusion and, via this adaptation, may support the storage of fatty acids in IMTG.

Because the lipid droplet (LD)‐associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, we investigated the hypothesis that differential protein content of PLINs and their distribution with LDs may be linked to the diverse lipid storage in muscle between trained and sedentary individuals. Trained (n = 11) and sedentary (n = 10) subjects, matched for age, sex and body mass index, received either a 6 h lipid or glycerol infusion in the setting of a concurrent hyperinsulinaemic–euglycaemic clamp. Sequential muscle biopsies (0, 2 and 6 h) were analysed using confocal immunofluorescence microscopy for fibre type‐specific IMTG content and PLIN associations with LDs. In both groups, lipid infusion increased IMTG content in type I fibres (trained: +62%, sedentary: +79%; P < 0.05) but did not affect PLIN protein content. At baseline, PLIN2 (+65%), PLIN3 (+105%) and PLIN5 (+53%; all P < 0.05) protein content was higher in trained compared to sedentary individuals. In trained individuals, lipid infusion increased the number of LDs associated with PLIN2 (+27%), PLIN3 (+73%) and PLIN5 (+40%; all P < 0.05) in type I fibres. By contrast, in sedentary individuals, lipid infusion only increased the number of LDs not associated with PLIN proteins. Acute free fatty acid elevation therefore induces a redistribution of PLIN proteins to an expanded LD pool in trained individuals only and this may be part of the mechanism that enables fatty acids to be stored in IMTG.
Ecto‐5′‐nucleotidase (CD73) regulates peripheral chemoreceptor activity and cardiorespiratory responses to hypoxia
Authors: Holmes Andrew P. , Ray Clare J. , Pearson Selina A. , Coney Andrew M. , Kumar Prem
Published: May 2017

Key points

Carotid body dysfunction is recognized as a cause of hypertension in a number of cardiorespiratory diseases states and has therefore been identified as a potential therapeutic target.

Purinergic transmission is an important element of the carotid body chemotransduction pathway.

We show that inhibition of ecto‐5′‐nucleotidase (CD73)in vitroreduces carotid body basal discharge and responses to hypoxia and mitochondrial inhibition.

Additionally, inhibition of CD73in vivodecreased the hypoxic ventilatory response, reduced the hypoxia‐induced heart rate elevation and exaggerated the blood pressure decrease in response to hypoxia.

Our data show CD73 to be a novel regulator of carotid body sensory function and therefore suggest that this enzyme may offer a new target for reducing carotid body activity in selected cardiovascular diseases.

Augmented sensory neuronal activity from the carotid body (CB) has emerged as a principal cause of hypertension in a number of cardiovascular related pathologies, including obstructive sleep apnoea, heart failure and diabetes. Development of new targets and pharmacological treatment strategies aiming to reduce CB sensory activity may thus improve outcomes in these key patient cohorts. The present study investigated whether ecto‐5′‐nucleotidase (CD73), an enzyme that generates adenosine, is functionally important in modifying CB sensory activity and cardiovascular respiratory responses to hypoxia. Inhibition of CD73 by α,β‐methylene ADP (AOPCP) in the whole CB preparationin vitroreduced basal discharge frequency by 76 ± 5% and reduced sensory activity throughout graded hypoxia. AOPCP also significantly attenuated elevations in sensory activity evoked by mitochondrial inhibition. These effects were mimicked by antagonism of adenosine receptors with 8‐(p‐sulfophenyl) theophylline. Infusion of AOPCPin vivosignificantly decreased the hypoxic ventilatory response (ΔEcontrol 74 ± 6%, ΔEAOPCP 64 ± 5%,P < 0.05). AOPCP also modified cardiovascular responses to hypoxia, as indicated by reduced elevations in heart rate and exaggerated changes in femoral vascular conductance and mean arterial blood pressure. Thus we identify CD73 as a novel regulator of CB sensory activity. Future investigations are warranted to clarify whether inhibition of CD73 can effectively reduce CB activity in CB‐mediated cardiovascular pathology.
Human melanoma inhibitory protein binds to the FN12-14 Hep II domain of fibronectin
Authors: Yip King Tuo , Zhong Xueyin , Seibel Nadia , Arnolds Oliver , Schöpel Miriam , Stoll Raphael
Published: May 2017

The heparin binding site (Hep II) of fibronectin plays a major role in tumor cell metastasis. Its interaction with heparan sulfate proteoglycans occurs in a variety of physiological processes including focal adhesion and migration. The melanoma inhibitory activity (MIA) is an important protein that is functionally involved in melanoma development, progression, and tumor cell invasion. After its secretion by malignant melanoma cells, MIA interacts with fibronectin and thereby actively facilitates focal cell detachment from surrounding structures and strongly promotes tumor cell invasion and the formation of metastases. In this report, the authors have determined the molecular basis of the interaction of MIA with the Hep II domain of fibronectin based on nuclear magnetic resonance spectroscopic binding assays. The authors have identified the type III modules 12 to 14 of fibronectin's Hep II as the major MIA binding sites. These results now provide a new target protein–protein binding interface for the discovery of novel antimetastatic agents against malignant melanoma in the future.
Occurrence of Plasmid- and Chromosome-Carried
mcr-1
in Waterborne Enterobacteriaceae in China
Authors: Zhou Hong-Wei , Zhang Ting , Ma Ji-Hua , Fang Ying , Wang Han-Yu , Huang Zi-Xian , Wang Yang , Wu Congming , Chen Gong-Xiang
Published: May 2017

The aim of this study was to investigate the prevalence of the polymyxin resistance gene
mcr-1
in
Enterobacteriaceae
from environmental water sources in Hangzhou, China. Colistin-resistant bacteria were isolated from environmental water samples using an enrichment broth culture method, were screened for
mcr-1
, and then were analyzed for the location and transferability of
mcr-1
. Isolates positive for
mcr-1
were further examined to determine their susceptibility profiles and were screened for the presence of additional resistance genes. Twenty-three
mcr-1
-positive isolates (16
Escherichia coli
, two
Citrobacter freundii
, two
Klebsiella oxytoca
, two
Citrobacter braakii
, and one
Enterobacter cloacae
) were isolated from 7/9 sampling locations; of those, eight
mcr-1
-positive isolates also contained β-lactamase-resistance genes, eight contained
qnrS
, and 10 contained
oqx
. No
mcr-2
-positive isolates were identified. The majority of isolates demonstrated a low to moderate level of colistin resistance. Transconjugation was successfully conducted from 14 of the 23
mcr-1
-positive isolates, and
mcr-1
was identified on plasmids ranging from 60 to 220 kb in these isolates. Conjugation and hybridization experiments revealed that
mcr-1
was chromosome-borne in only three isolates. Pulsed-field gel electrophoresis showed that the majority of
E. coli
isolates belonged to different clonal lineages. Multilocus sequence typing analysis revealed that sequence type 10 (ST10) was the most prevalent, followed by ST181 and ST206. This study demonstrates the utility of enrichment broth culture for identifying environmental
mcr-1
-positive isolates. Furthermore, it highlights the importance of responsible agriculture and clinical use of polymyxins to prevent further widespread dissemination of polymyxin-resistant pathogens.
Human Bile Reduces Antimicrobial Activity of Selected Antibiotics against Enterococcus faecalis and Escherichia coli
In Vitro
Authors: Wulkersdorfer Beatrix , Jaros David , Eberl Sabine , Poschner Stefan , Jäger Walter , Cosentini Enrico , Zeitlinger Markus , Schwameis Richard
Published: May 2017

It has been known from previous studies that body fluids, such as cerebrospinal fluid, lung surfactant, and urine, have a strong impact on the bacterial killing of many anti-infective agents. However, the influence of human bile on the antimicrobial activity of antibiotics is widely unknown. Human bile was obtained and pooled from 11 patients undergoing cholecystectomy. After sterilization of the bile fluid by gamma irradiation, its effect on bacterial killing was investigated for linezolid (LZD) and tigecycline (TGC) against
Enterococcus faecalis
ATCC 29212. Further, ciprofloxacin (CIP), meropenem (MEM), and TGC were tested against
Escherichia coli
ATCC 25922. Time-kill curves were performed in pooled human bile and Mueller-Hinton broth (MHB) over 24 h. Bacterial counts (in CFU per milliliter after 24 h) of bile growth controls were approximately equal to MHB growth controls for
E. coli
and approximately 2-fold greater for
E. faecalis
, indicating a promotion of bacterial growth by bile for the latter strain. Bile reduced the antimicrobial activity of CIP, MEM, and TGC against
E. coli
as well as the activity of LZD and TGC against
E. faecalis
. This effect was strongest for TGC against the two strains. Degradation of TGC in bile was identified as the most likely explanation. These findings may have important implications for the treatment of bacterial infections of the gallbladder and biliary tract and should be explored in more detail.
Ceftazidime-Avibactam Is Superior to Other Treatment Regimens against Carbapenem-Resistant Klebsiella pneumoniae Bacteremia
Authors: Shields Ryan K. , Nguyen M. Hong , Chen Liang , Press Ellen G. , Potoski Brian A. , Marini Rachel V. , Doi Yohei , Kreiswirth Barry N. , Clancy Cornelius J.
Published: May 2017

There are no data comparing outcomes of patients treated with ceftazidime-avibactam versus comparators for carbapenem-resistant
Enterobacteriaceae
infections. At our center, ceftazidime-avibactam treatment of carbapenem-resistant
Klebsiella pneumoniae
bacteremia was associated with higher rates of clinical success (
P
= 0.006) and survival (
P
= 0.01) than other regimens. Across treatment groups, there were no differences in underlying diseases, severity of illness, source of bacteremia, or strain characteristics (97% produced
K. pneumoniae
carbapenemase). Aminoglycoside- and colistin-containing regimens were associated with increased rates of nephrotoxicity (
P
= 0.002).
Synergistic Activity between Statins and Bisphosphonates against Acute Experimental Toxoplasmosis
Authors: Li Zhu-Hong , Li Catherine , Szajnman Sergio H. , Rodriguez Juan B. , Moreno Silvia N. J.
Published: May 2017

Bisphosphonates are widely used for the treatment of bone disorders. These drugs also inhibit the growth of a variety of protozoan parasites, such as
Toxoplasma gondii
, the etiologic agent of toxoplasmosis. The target of the most potent bisphosphonates is the isoprenoid biosynthesis pathway enzyme farnesyl diphosphate synthase (FPPS). Based on our previous work on the inhibitory effect of sulfur-containing linear bisphosphonates against
T. gondii
, we investigated the potential synergistic interaction between one of these derivatives, 1-[(
n
-heptylthio)ethyl]-1,1-bisphosphonate (C7S), and statins, which are potent inhibitors of the host 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (3-HMG-CoA reductase). C7S showed high activity against the
T. gondii
bifunctional farnesyl diphosphate (FPP)/geranylgeranyl diphosphate (GGPP) synthase (TgFPPS), which catalyzes the formation of FPP and GGPP (50% inhibitory concentration [IC
50
] = 31 ± 0.01 nM [mean ± standard deviation]), and modest effect against the human FPPS (IC
50
= 1.3 ± 0.5 μM). We tested combinations of C7S with statins against the
in vitro
replication of
T. gondii
. We also treated mice infected with a lethal dose of
T. gondii
with similar combinations. We found strong synergistic activities when using low doses of C7S, which were stronger
in vivo
than when tested
in vitro
. We also investigated the synergism of several commercially available bisphosphonates with statins both
in vitro
and
in vivo
. Our results provide evidence that it is possible to develop drug combinations that act synergistically by inhibiting host and parasite enzymes
in vitro
and in
vivo
.
The Bordetella Bps Polysaccharide Is Required for Biofilm Formation and Enhances Survival in the Lower Respiratory Tract of Swine
Authors: Nicholson Tracy L. , Brockmeier Susan L. , Sukumar Neelima , Paharik Alexandra E. , Lister Jessica L. , Horswill Alexander R. , Kehrli Marcus E. , Loving Crystal L. , Shore Sarah M. , Deora Rajendar
Published: May 2017

Bordetella bronchiseptica
is pervasive in swine populations and plays multiple roles in respiratory disease. Additionally,
B. bronchiseptica
is capable of establishing long-term or chronic infections in swine. Bacterial biofilms are increasingly recognized as important contributors to chronic bacterial infections. Recently the polysaccharide locus
bpsABCD
has been demonstrated to serve a critical role in the development of mature biofilms formed by the sequenced laboratory strain of
B. bronchiseptica
. We hypothesized that swine isolates would also have the ability to form mature biofilms and the
bpsABCD
locus would serve a key role in this process. A mutant containing an in-frame deletion of the
bpsABCD
structural genes was constructed in a wild-type swine isolate and found to be negative for poly-N-acetylglucosamine (PNAG)-like material by immunoblot assay. Further, the
bpsABCD
locus was found to be required for the development and maintenance of the three-dimensional structures under continuous-flow conditions. To investigate the contribution of the
bpsABCD
locus to the pathogenesis of
B. bronchiseptica
in swine, the KM22Δ
bps
mutant was compared to the wild-type swine isolate for the ability to colonize and cause disease in pigs. The
bpsABCD
locus was found to not be required for persistence in the upper respiratory tract of swine. Additionally, the
bpsABCD
locus did not affect the development of anti-
Bordetella
humoral immunity, did not contribute to disease severity, and did not mediate protection from complement-mediated killing. However, the
bpsABCD
locus was found to enhance survival in the lower respiratory tract of swine.
Phylogenetic and Structural Comparisons of the Three Types of Methyl Coenzyme M Reductase from Methanococcales and Methanobacteriales
Authors: Wagner Tristan , Wegner Carl-Eric , Kahnt Jörg , Ermler Ulrich , Shima Seigo
Published: May 2017

The phylogenetically diverse family of methanogenic archaea universally use methyl coenzyme M reductase (MCR) for catalyzing the final methane-forming reaction step of the methanogenic energy metabolism. Some methanogens of the orders
Methanobacteriales
and
Methanococcales
contain two isoenzymes. Comprehensive phylogenetic analyses on the basis of all three subunits grouped MCRs from
Methanobacteriales
and
Methanococcales
into three distinct types: (i) MCRs from
Methanobacteriales
, (ii) MCRs from
Methanobacteriales
and
Methanococcales
, and (iii) MCRs from
Methanococcales
. The first and second types contain MCR isoenzymes I and II from
Methanothermobacter marburgensis
, respectively; therefore, they were designated MCR type I and type II and accordingly; the third one was designated MCR type III. For comparison with the known MCR type I and type II structures, we determined the structure of MCR type III from
Methanotorris formicicus
and
Methanothermococcus thermolithotrophicus
. As predicted, the three MCR types revealed highly similar overall structures and virtually identical active site architectures reflecting the chemically challenging mechanism of methane formation. Pronounced differences were found at the protein surface with respect to loop geometries and electrostatic properties, which also involve the entrance of the active-site funnel. In addition, the C-terminal end of the γ-subunit is prolonged by an extra helix after helix γ8 in MCR type II and type III, which is, however, differently arranged in the two MCR types. MCR types I, II, and III share most of the posttranslational modifications which appear to fine-tune the enzymatic catalysis. Interestingly, MCR type III lacks the methyl-cysteine but possesses in subunit α of
M. formicicus
a 6-hydroxy-tryptophan, which thus far has been found only in the α-amanitin toxin peptide but not in proteins.

IMPORTANCE
Methyl coenzyme M reductase (MCR) represents a prime target for the mitigation of methane releases. Phylogenetic analyses of MCRs suggested several distinct sequence clusters; those from
Methanobacteriales
and
Methanococcales
were subdivided into three types: MCR type I from
Methanobacteriales
, MCR type II from
Methanobacteriales
and
Methanococcales
, and the newly designated MCR type III exclusively from
Methanococcales
. We determined the first X-ray structures for an MCR type III. Detailed analyses revealed substantial differences between the three types only in the peripheral region. The subtle modifications identified and electrostatic profiles suggested enhanced substrate binding for MCR type III. In addition, MCR type III from
Methanotorris formicicus
contains 6-hydroxy-tryptophan, a new posttranslational modification that thus far has been found only in the α-amanitin toxin.
A Conserved Metal Binding Motif in the Bacillus subtilis Competence Protein ComFA Enhances Transformation
Authors: Chilton Scott S. , Falbel Tanya G. , Hromada Susan , Burton Briana M.
Published: May 2017

Genetic competence is a process in which cells are able to take up DNA from their environment, resulting in horizontal gene transfer, a major mechanism for generating diversity in bacteria. Many bacteria carry homologs of the central DNA uptake machinery that has been well characterized in
Bacillus subtilis
. It has been postulated that the
B. subtilis
competence helicase ComFA belongs to the DEAD box family of helicases/translocases. Here, we made a series of mutants to analyze conserved amino acid motifs in several regions of
B. subtilis
ComFA. First, we confirmed that ComFA activity requires amino acid residues conserved among the DEAD box helicases, and second, we show that a zinc finger-like motif consisting of four cysteines is required for efficient transformation. Each cysteine in the motif is important, and mutation of at least two of the cysteines dramatically reduces transformation efficiency. Further, combining multiple cysteine mutations with the helicase mutations shows an additive phenotype. Our results suggest that the helicase and metal binding functions are two distinct activities important for ComFA function during transformation.

IMPORTANCE
ComFA is a highly conserved protein that has a role in DNA uptake during natural competence, a mechanism for horizontal gene transfer observed in many bacteria. Investigation of the details of the DNA uptake mechanism is important for understanding the ways in which bacteria gain new traits from their environment, such as drug resistance. To dissect the role of ComFA in the DNA uptake machinery, we introduced point mutations into several motifs in the protein sequence. We demonstrate that several amino acid motifs conserved among ComFA proteins are important for efficient transformation. This report is the first to demonstrate the functional requirement of an amino-terminal cysteine motif in ComFA.
A Screen for
rfaH
Suppressors Reveals a Key Role for a Connector Region of Termination Factor Rho
Authors: Hu Kuang , Artsimovitch Irina
Published: May 2017

RfaH activates horizontally acquired operons that encode lipopolysaccharide core components, pili, toxins, and capsules. Unlike its paralog NusG, which potentiates Rho-mediated silencing, RfaH strongly inhibits Rho. RfaH is recruited to its target operons via a network of contacts with an elongating RNA polymerase (RNAP) and a specific DNA element called
ops
to modify RNAP into a pause- and NusG-resistant state.
rfaH
null mutations confer hypersensitivity to antibiotics and detergents, altered susceptibility to bacteriophages, and defects in virulence. Here, we carried out a selection for suppressors that restore the ability of a Δ
rfaH
mutant
Escherichia coli
strain to grow in the presence of sodium dodecyl sulfate. We isolated
rho
,
rpoC
, and
hns
suppressor mutants with changes in regions previously shown to be important for their function. In addition, we identified mutants with changes in an unstructured region that connects the primary RNA-binding and helicase domains of Rho. The connector mutants display strong defects
in vivo
, consistent with their ability to compensate for the loss of RfaH, and act synergistically with bicyclomycin (BCM), which has been recently shown to inhibit Rho transformation into a translocation-competent state. We hypothesize that the flexible connector permits the reorientation of Rho domains and serves as a target for factors that control the motor function of Rho allosterically. Our results, together with the existing data, support a model in which the connector segment plays a hitherto overlooked role in the regulation of Rho-dependent termination.

IMPORTANCE
The transcription termination factor Rho silences foreign DNA, reduces antisense transcription, mediates surveillance of mRNA quality, and maintains genome integrity by resolving transcription-replication collisions and deleterious R loops. Upon binding to RNA, Rho undergoes a rate-limiting transition from an open “lock washer” state to a closed ring capable of processive translocation on, and eventually the release of, the nascent transcript. Recent studies revealed that Rho ligands, including its cofactor NusG and inhibitor bicyclomycin, control the ring dynamics allosterically. In this work, we used a genetic selection for suppressors of RfaH, a potent inhibitor of Rho, to isolate a new class of mutations in a flexible region that connects the primary RNA-binding and ATPase/translocase domains of Rho. We propose that the connector is essential for the modulation of Rho activity by different RNA sequences and accessory proteins.
Significant Impacts of Increasing Aridity on the Arid Soil Microbiome
Authors: Neilson Julia W. , Califf Katy , Cardona Cesar , Copeland Audrey , van Treuren Will , Josephson Karen L. , Knight Rob , Gilbert Jack A. , Quade Jay , Caporaso J. Gregory , Maier Raina M.
Published: May 2017

We identify key environmental and geochemical factors that shape the arid soil microbiome along aridity and vegetation gradients spanning over 300 km of the Atacama Desert, Chile. Decreasing average soil relative humidity and increasing temperature explain significant reductions in the diversity and connectivity of these desert soil microbial communities and lead to significant reductions in the abundance of key taxa typically associated with fertile soils. This finding is important because it suggests that predicted climate change-driven increases in aridity may compromise the capacity of the arid-soil microbiome to sustain necessary nutrient cycling and carbon sequestration functions as well as vegetative cover in desert ecosystems, which comprise one-third of the terrestrial biomes on Earth.
Linagliptin-associated blistering and ulceration
Authors: Psomadakis Cristina , Shahzad Naima , Katz Jonathan
Published: May 2017

We present the case of 60-year-old man with type 2 diabetes who developed blistering after two sequential exposures to linagliptin. Linagliptin is one of the dipeptidyl peptidase 4 (DPP-4) inhibitors, a group of oral hypoglycaemic agents used commonly for the treatment of type 2 diabetes. On the first exposure to linagliptin, he developed blisters on the hands which resolved after stopping the drug. After repeat exposure, he developed two large blisters on the left foot, which burst giving rise to secondary infection, requiring hospital admission for treatment. We discuss the latest research linking DPP-4 inhibitors with adverse skin reactions and the effect of ulcers on the morbidity and mortality of patients with diabetes. This case report highlights skin reactions as an important, rare and lesser known side effect of DPP-4 inhibitors.
Predictors of clinical recovery from concussion: a systematic review
Authors: Iverson Grant L , Gardner Andrew J , Terry Douglas P , Ponsford Jennie L , Sills Allen K , Broshek Donna K , Solomon Gary S
Published: May 2017

Objective

A systematic review of factors that might be associated with, or influence, clinical recovery from sport-related concussion. Clinical recovery was defined functionally as a return to normal activities, including school and sports, following injury.

Design

Systematic review.

Data sources

PubMed, PsycINFO, MEDLINE, CINAHL, Cochrane Library, EMBASE, SPORTDiscus, Scopus and Web of Science.

Eligibility criteria for selecting studies

Studies published by June of 2016 that addressed clinical recovery from concussion.

Results

A total of 7617 articles were identified using the search strategy, and 101 articles were included. There are major methodological differences across the studies. Many different clinical outcomes were measured, such as symptoms, cognition, balance, return to school and return to sports, although symptom outcomes were the most frequently measured. The most consistent predictor of slower recovery from concussion is the severity of a person’s acute and subacute symptoms. The development of subacute problems with headaches or depression is likely a risk factor for persistent symptoms lasting greater than a month. Those with a preinjury history of mental health problems appear to be at greater risk for having persistent symptoms. Those with attention deficit hyperactivity disorder (ADHD) or learning disabilities do not appear to be at substantially greater risk. There is some evidence that the teenage years, particularly high school, might be the most vulnerable time period for having persistent symptoms—with greater risk for girls than boys.

Conclusion

The literature on clinical recovery from sport-related concussion has grown dramatically, is mostly mixed, but some factors have emerged as being related to outcome.
Cost and Efficacy Examination of Alvimopan for the Prevention of Postoperative Ileus
Authors: Nemeth Zoltan H , Bogdanovski Dorian A , Paglinco Samantha R , Barratt-Stopper Patricia , Rolandelli Rolando H
Published: May 2017

Opioid analgesics exacerbate ileus through peripheral μ-opioid receptor action. Alvimopan, a μ-opioid receptor antagonist, has been proposed to alleviate postoperative ileus, leading to decreased time to return of gastrointestinal function and hospital discharge. As opioid-induced motility issues are only one factor affecting postoperative ileus, continued examination of the cost of the use and efficacy of the drug is needed. Data for this study were collected retrospectively from the charts of 55 patients who received an anastomosis and were given alvimopan at Morristown Medical Center between 2010 and 2013 as well as from 58 appropriately matched controls. The billing record and chart for each patient was examined, and information on total hospital charges, age, sex, body mas index, primary diagnosis, procedure type, length of stay (days), time to return of bowel function (hours), and outcomes were recorded for analysis. No difference between patients given alvimopan and controls was observed for the length of hospital stay (4.6 vs 4.8 days) or for time to return of bowel function (68.5 vs 67.3 hours). Total hospital charges were higher for treated patients (p=0.0080), averaging $48 705.15 and $41 068.80, respectively. Alvimopan was not associated with improved clinical outcome but was associated with an increase in hospital charges within this population.
Interpretation of vane shear tests for geotechnical stability calculations
Authors: Kouretzis George , Pineda Jubert , Krabbenhøft Kristian , Wilson Lachlan
Published: May 2017

In this note we consider the problem of calibrating failure criteria for short-term stability calculations based on the results of vane shear tests. Numerical and theoretical considerations supported by experimental data provide evidence that we can use the vane shear test to obtain the undrained strength of a sample tested under simple shear conditions at a normal stress equal to the horizontal effective stress at the given depth. Consequently, it is argued that there is no need to correct the field vane undrained strength to obtain the mobilized strength for embankment stability calculations, provided that soil strength is normalized to the normal effective stress acting on the slip surface and rate effects are properly considered. We further show that the standard Tresca failure criterion, albeit simplistic, will provide reasonable estimates of the mobilized strength if properly calibrated against field vane tests.
Noise-enhanced CVQKD with untrusted source
Authors: Wang Xiaoqun , Huang Chunhui
Published: May 2017

The performance of one-way and two-way continuous variable quantum key distribution (CVQKD) protocols can be increased by adding some noise on the reconciliation side. In this paper, we propose to add noise at the reconciliation end to improve the performance of CVQKD with untrusted source. We derive the key rate of this case and analyze the impact of the additive noise. The simulation results show that the optimal additive noise can improve the performance of the system in terms of maximum transmission distance and tolerable excess noise.
Integrated Circuit with Memristor Emulator Array and Neuron Circuits for Biologically Inspired Neuromorphic Pattern Recognition
Authors: Ranjan Rajeev , Ponce Pablo Mendoza , Hellweg Wolf Lukas , Kyrmanidis Alexandros , Saleh Lait Abu , Schroeder Dietmar , Krautschneider Wolfgang H.
Published: May 2017

This paper details an application-specific integrated circuit (ASIC) with an array of switched-resistor-based memristors (resistor with memory) and integrate & fire (I & F) neuron circuits for the development of memristor-based pattern recognition. Since real memristors are not commercially available, a compact memristor emulator is needed for device study. The designed ASIC has five memristor emulators with one having a conductance range from 4.88[Formula: see text]ns to 4.99[Formula: see text][Formula: see text]s (200[Formula: see text]k[Formula: see text] to 204.8[Formula: see text]M[Formula: see text]) and other four having conductance ranging from 195[Formula: see text]ns to 190[Formula: see text][Formula: see text]s (5.2[Formula: see text]k[Formula: see text] to 5.12[Formula: see text]M[Formula: see text]). Signal processing has been planned to be off-chip to get the freedom of programmability of a wide range of memristive behavior. This paper introduces the memristor emulator and the realization of synapse functionalities used in neuromorphic circuits such as long term potentiation (LTP), Long Term depression (LTD) and synaptic plasticity. The ASIC has two I & F neuron circuits which are intended to be used in conjunction with memristors in a multiple chip network for pattern recognition. This paper explains the memristor emulator, I & F neuron circuit and a respective neuromorphic system for pattern recognition simulated in LTspice. The ASIC has been fabricated in AMS 350[Formula: see text]nm process.
Analytic characterizations of infinite dimensional distributions
Authors: Accardi Luigi , Ji Un Cig , Saitô Kimiaki
Published: May 2017

We revisit the analytic characterization theorem for S-transform of infinite dimensional distributions. Then we prove that the nuclearity of the space of test white noise functionals is a necessary condition for the characterization of the S-transform in terms of analytic and growth conditions.
INTERNET OF THINGS BUSINESS MODEL INNOVATION AND THE STAGE-GATE PROCESS: AN EXPLORATORY ANALYSIS
Authors: TESCH JAN F. , BRILLINGER ANNE-SOPHIE , BILGERI DOMINIK
Published: May 2017

Large manufacturing companies will in future be continuously challenged to develop and implement new IoT-related business models. Existing research offers interesting insights on high-level stages of business model innovation (BMI) processes in general. However, only little is known about the presence of main gates in BMI processes and even less about the underlying decision criteria applied at these gates. To shed more light on this research field, 27 expert interviews with employees from eight companies across the IoT ecosystem were conducted. The expert interviews reveal that, despite the increasing popularity of (radically) new innovation approaches, two main decision points can be identified across BMI processes. These findings are a first explorative step towards a better understanding of IoT adoption and provide a starting point for interesting future research avenues.
Hypoxia impairs mesenchymal stromal cell-induced macrophage M1 to M2 transition
Authors: Faulknor Renea A. , Olekson Melissa A. , Ekwueme Emmanuel C. , Krzyszczyk Paulina , Freeman Joseph W. , Berthiaume François
Published: May 2017

The transition of macrophages from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype is crucial for the progression of normal wound healing. Persistent M1 macrophages within the injury site may lead to an uncontrolled macrophage-mediated inflammatory response and ultimately a failure of the wound healing cascade, leading to chronic wounds. Mesenchymal stromal cells (MSCs) have been widely reported to promote M1 to M2 macrophage transition; however, it is unclear whether MSCs can drive this transition in the hypoxic environment typically observed in chronic wounds. Here we report on the effect of hypoxia (1% O[Formula: see text] on MSCs’ ability to transition macrophages from the M1 to the M2 phenotype. While hypoxia had no effect on MSC secretion, it inhibited MSC-induced M1 to M2 macrophage transition, and suppressed macrophage expression and production of the anti-inflammatory mediator interleukin-10 (IL-10). These results suggest that hypoxic environments may impede the therapeutic effects of MSCs.
Petri Net Models and Collaborativeness for Parallel Processes with Resource Sharing and Message Passing
Authors: Liu Guanjun , Zhou Mengchu , Jiang Changjun
Published: May 2017

Petri nets are widely used to model and analyse concurrent systems. There exist two distinct classes of Petri nets that focus on different features of concurrent systems. The first one features multiple parallel processes sharing a group of common resources but not interacting/collaborating with each other. The second one allows multiple parallel processes to interact/collaborate with each other via message exchange but does not share any common resources. However, in many distributed environments, multiple processes both interact/collaborate with each other and share some common resources. To model and analyse such systems, this article defines a new class of Petri nets called
Parallel Process Nets
(P
2
Ns) that may be viewed as a generalization of the two mentioned above. We propose
collaborativeness
and
close collaborativeness
for P
2
Ns. The former guarantees that a modelled system is both deadlock-free and livelock-free, and the latter guarantees that it is deadlock-free, livelock-free, and starvation-free. These concepts and ideas are illustrated through some classical examples such as Producer-Consumer Problem and Dinning Philosophers Problem. Algorithms are developed to decide them. At last, P
2
Ns are applied to the modelling and analysis of two real systems: hospital information system and elevator scheduling system.
Distributed Multi-Representative Re-Fusion Approach for Heterogeneous Sensing Data Collection
Authors: Liu Anfeng , Liu Xiao , Wei Tianyi , Yang Laurence T. , Rho Seungmin (Charlie) , Paul Anand
Published: May 2017

A multi-representative re-fusion (MRRF) approximate data collection approach is proposed in which multiple nodes with similar readings form a data coverage set (DCS). The reading value of the DCS is represented by an R-node. The set near the Sink is smaller, while the set far from the Sink is larger, which can reduce the energy consumption in hotspot areas. Then, a distributed data-aggregation strategy is proposed that can re-fuse the value of R-nodes that are far from each other but have similar readings. Both comprehensive theoretical and experimental results indicate that the MRRF approach increases lifetime and energy efficiency.
Schedulability of Bounded-Rate Multimode Systems
Authors: Alur Rajeev , Forejt Vojtěch , Moarref Salar , Trivedi Ashutosh
Published: May 2017

Bounded-rate multimode systems are hybrid systems that switch freely among a finite set of modes, and whose dynamics are specified by a finite number of real-valued variables with mode-dependent rates that vary within given bounded sets. The scheduler repeatedly proposes a time and a mode, while the environment chooses an allowable rate for that mode; the state of the system changes linearly in the direction of the rate. The scheduler aims to keep the state within a safe set, while the environment aims to leave it. We study the problem of existence of a winning scheduler strategy and associated complexity questions.
A Fine-Grain Time-Sharing Time Warp System
Authors: Pellegrini Alessandro , Quaglia Francesco
Published: May 2017

Several techniques have been proposed to improve the performance of Parallel Discrete Event Simulation platforms relying on the Time Warp (optimistic) synchronization protocol. Among them we can mention optimized approaches for state restore, as well as techniques for load balancing or (dynamically) controlling the speculation degree, the latter being specifically targeted at reducing the incidence of causality errors leading to waste of computation. However, in state-of-the-art Time Warp systems, events’ processing is not preemptable, which may prevent the possibility to promptly react to the injection of higher priority (say, lower timestamp) events. Delaying the processing of these events may, in turn, give rise to higher incidence of incorrect speculation. In this article, we present the design and realization of a fine-grain time-sharing Time Warp system, to be run on multi-core Linux machines, which makes systematic use of event preemption in order to dynamically reassign the CPU to higher priority events/tasks. Our proposal is based on a truly dual mode execution, application versus platform, which includes a timer-interrupt-based support for bringing control back to platform mode for possible CPU reassignment according to very fine grain periods. The latter facility is offered by an ad-hoc timer-interrupt management module for Linux, which we release, together with the overall time-sharing support, within the open source ROOT-Sim platform. An experimental assessment based on the classical PHOLD benchmark and two real-world models is presented, which shows how our proposal effectively leads to the reduction of the incidence of causality errors, especially when running with higher degrees of parallelism.
An Integrated Vector-Scalar Design on an In-Order ARM Core
Authors: Stanic Milan , Palomar Oscar , Hayes Timothy , Ratkovic Ivan , Cristal Adrian , Unsal Osman , Valero Mateo
Published: May 2017

In the low-end mobile processor market, power, energy, and area budgets are significantly lower than in the server/desktop/laptop/high-end mobile markets. It has been shown that vector processors are a highly energy-efficient way to increase performance; however, adding support for them incurs area and power overheads that would not be acceptable for low-end mobile processors. In this work, we propose an integrated vector-scalar design for the ARM architecture that mostly reuses scalar hardware to support the execution of vector instructions. The key element of the design is our proposed block-based model of execution that groups vector computational instructions together to execute them in a coordinated manner. We implemented a classic vector unit and compare its results against our integrated design. Our integrated design improves the performance (more than 6×) and energy consumption (up to 5×) of a scalar in-order core with negligible area overhead (only 4.7% when using a vector register with 32 elements). In contrast, the area overhead of the classic vector unit can be significant (around 44%) if a dedicated vector floating-point unit is incorporated. Our block-based vector execution outperforms the classic vector unit for all kernels with floating-point data and also consumes less energy. We also complement the integrated design with three energy/performance-efficient techniques that further reduce power and increase performance. The first proposal covers the design and implementation of chaining logic that is optimized to work with the cache hierarchy through vector memory instructions, the second proposal reduces the number of reads/writes from/to the vector register file, and the third idea optimizes complex memory access patterns with the memory shape instruction and unified indexed vector load.
Predicting Query Quality for Applications of Text Retrieval to Software Engineering Tasks
Authors: Mills Chris , Bavota Gabriele , Haiduc Sonia , Oliveto Rocco , Marcus Andrian , Lucia Andrea De
Published: May 2017

Context:
Since the mid-2000s, numerous recommendation systems based on text retrieval (TR) have been proposed to support software engineering (SE) tasks such as concept location, traceability link recovery, code reuse, impact analysis, and so on. The success of TR-based solutions highly depends on the query submitted, which is either formulated by the developer or automatically extracted from software artifacts.

Aim:
We aim at predicting the quality of queries submitted to TR-based approaches in SE. This can lead to benefits for developers and for the quality of software systems alike. For example, knowing when a query is poorly formulated can save developers the time and frustration of analyzing irrelevant search results. Instead, they could focus on reformulating the query. Also, knowing if an artifact used as a query leads to irrelevant search results may uncover underlying problems in the query artifact itself.

Method:
We introduce an automatic query quality prediction approach for software artifact retrieval by adapting NL-inspired solutions to their use on software data. We present two applications and evaluations of the approach in the context of concept location and traceability link recovery, where TR has been applied most often in SE. For concept location, we use the approach to determine if the list of retrieved code elements is likely to contain code relevant to a particular change request or not, in which case, the queries are good candidates for reformulation. For traceability link recovery, the queries represent software artifacts. In this case, we use the query quality prediction approach to identify artifacts that are hard to trace to other artifacts and may therefore have a low intrinsic quality for TR-based traceability link recovery.

Results:
For concept location, the evaluation shows that our approach is able to correctly predict the quality of queries in 82% of the cases, on average, using very little training data. In the case of traceability recovery, the proposed approach is able to detect hard to trace artifacts in 74% of the cases, on average.

Conclusions:
The results of our evaluation on applications for concept location and traceability link recovery indicate that our approach can be used to predict the results of a TR-based approach by assessing the quality of the text query. This can lead to saved effort and time, as well as the identification of software artifacts that may be difficult to trace using TR.
Tight Bounds on Vertex Connectivity Under Sampling
Authors: Censor-Hillel Keren , Ghaffari Mohsen , Giakkoupis George , Haeupler Bernhard , Kuhn Fabian
Published: May 2017

A fundamental result by Karger [10] states that for any λ-edge-connected graph with
n
nodes, independently sampling each edge with probability
p
= Ω(log (
n
)/λ) results in a graph that has edge connectivity Ω(λ
p
), with high probability. This article proves the analogous result for vertex connectivity, when either vertices or edges are sampled. We show that for any
k
-vertex-connected graph
G
with
n
nodes, if each node is independently sampled with probability
p
=Ω(√log(
n
)/
k
), then the subgraph induced by the sampled nodes has vertex connectivity Ω(
kp
2
), with high probability. If edges are sampled with probability
p
= Ω(log (
n
)/
k
), then the sampled subgraph has vertex connectivity Ω(
kp
), with high probability. Both bounds are existentially optimal.