bluuebunny/crossref_metadata_2025 huggingface dataset:
Eyewitness recall and suggestibility in individuals with Down syndrome
Authors: Collins D. , Henry L.
Published: July 2016

Background

Many criminal justice professionals perceive the eyewitness skills of individuals with intellectual disabilities to be weaker than those of typically developing (TD) individuals. Down syndrome (DS) is one of the most common genetic causes of intellectual disabilities, yet there is no research addressing eyewitness skills in this population. This study examined the eyewitness recall and suggestibility of young people with DS.

Method

Young people with DS and mental age‐matched TD children viewed a video of a non‐violent petty crime and were subsequently asked to freely recall the event before being asked general and specific questions incorporating both misleading and non‐leading prompts.

Results

Compared with mental age‐matched TD individuals, young people with DS produced as much information, were just as accurate and were no more suggestible.

Conclusions

The eyewitness memory skills of young people with DS are comparable to those of mental age‐matched TD children. The implications of these findings for the forensic context and eyewitness memory are discussed.
Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b – implication in the pathogenesis of Parkinson's disease
Authors: Yang Tien‐Chun , Wu Pei‐Chun , Chung I‐Fang , Jiang Jhih‐Hang , Fann Ming‐Ji , Kao Lung‐Sen
Published: July 2016

The pathogenesis of Parkinson's disease (PD) is not completely understood, Zinc (Zn2+) and dopamine (DA) have been shown to involve in the degeneration of dopaminergic cells. By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn2+ and DA‐induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn2+ treatment and raised to an even higher level by Zn2+ plus DA treatment. Zn2+ plus DA treatment‐induced PC12 cell death was enhanced when there was over‐expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross‐talk with Gadd45b during Zn2+ and DA treatment. The synergistic effects of Zn2+ and DA on PC12 cell death can be accounted for by an activation of the Gadd45b‐induced cell death pathway and an inhibition of p38/JNK survival pathway. Furthermore, the in vivo results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn2+/DA in the mouse brain and the level of Gadd45b mRNA is significantly higher in the substantia nigra of male PD patients than normal controls. The novel role of Gadd45b and its interactions with JNK and p38 will help our understanding of the pathogenesis of PD and help the development of future treatments for PD.

image

Zinc and dopamine are implicated in the degeneration of dopaminergic neurons. We previously demonstrated that zinc and dopamine induced synergistic effects on PC12 cell death. Results from this study show that these synergistic effects can be accounted for by activation of the Gadd45b‐induced cell death pathway and inhibition of the p38/JNK survival pathway. We provide in vitro and in vivo evidence to support a novel role for Gadd45b in the pathogenesis of Parkinson's disease.
Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system
Authors: Planells‐Ferrer Laura , Urresti Jorge , Coccia Elena , Galenkamp Koen M. O. , Calleja‐Yagüe Isabel , López‐Soriano Joaquín , Carriba Paulina , Barneda‐Zahonero Bruna , Segura Miguel F. , Comella Joan X.
Published: July 2016

The importance of death receptor (DR) signaling in embryonic development and physiological homeostasis is well established, as is the existence of several molecules that modulate DRs function, among them Fas Apoptotis Inhibitory Molecules. Although FAIM1, FAIM2, and FAIM3 inhibit Fas‐induced cell death, they are not structurally related, nor do they share expression patterns. Moreover, they inhibit apoptosis through completely different mechanisms. FAIM1 and FAIM2 protect neurons from DR‐induced apoptosis and are involved in neurite outgrowth and neuronal plasticity. FAIM1 inhibits Fas ligand‐ and tumor necrosis factor alpha‐induced apoptosis by direct interaction with Fas receptor and through the stabilization of levels of X‐linked inhibitor of apoptosis protein, a potent anti‐apoptotic protein that inhibits caspases. Low FAIM1 levels are found in Alzheimer's disease, thus sensitizing neurons to tumor necrosis factor alpha and prompting neuronal loss. FAIM2 protects from Fas by direct interaction with Fas receptor, as well as by modulating calcium release at the endoplasmic reticulum through interaction with Bcl‐xL. Several studies prove the role of FAIM2 in diseases of the nervous system, such as ischemia, bacterial meningitis, and neuroblastoma. The less characterized member of the FAIM family is FAIM3, which is expressed in tissues of the digestive and urinary tracts, bone marrow and testes, and restricted to the cerebellum in the nervous system. FAIM3 protects against DR‐induced apoptosis by inducing the expression of other DR‐antagonists such as CFLAR or through the interaction with the DR‐adaptor protein Fas‐associated via death domain. FAIM3 null mouse models reveal this protein as an important mediator of inflammatory autoimmune responses such as those triggered in autoimmune encephalomyelitis. Given the differences between FAIMs and the variety of processes in which they are involved, here we sought to provide a concise review about these molecules and their roles in the physiology and pathology of the nervous system.

image

Even though they share name and inhibit Fas‐induced cell death, Fas apoptotic inhibitory molecules (FAIMs) are not structurally related and inhibit apoptosis through completely different mechanisms. In this review, we describe FAIM1, FAIM2, and FAIM3 functions in the nervous system, and their implication in diverse pathologies such as neurodegenerative disease, cancer, or autoimmune diseases.
Developmental dynamics of occipital and cervical somites
Authors: Maschner Anja , Krück Stefanie , Draga Margarethe , Pröls Felicitas , Scaal Martin
Published: July 2016

Development of somites leading to somite compartments, sclerotome, dermomyotome and myotome, has been intensely investigated. Most knowledge on somite development, including the commonly used somite maturation stages, is based on data from somites at thoracic and lumbar levels. Potential regional differences in somite maturation dynamics have been indicated by a number of studies, but have not yet been comprehensively examined. Here, we present an overview on the developmental dynamics of somites at occipital and cervical levels in the chicken embryo. We show that in these regions, the onset of sclerotomal and myotomal compartment formation is later than at thoracolumbar levels, and is initiated simultaneously in multiple somites, which is in contrast to the serial cranial‐ to‐ caudal progression of somite maturation in the trunk. Our data suggest a variant spatiotemporal regulation of somite development in occipitocervical somites.
An interactive ICT platform for early assessment and management of patient‐reported concerns among older adults living in ordinary housing – development and feasibility
Authors: Algilani Samal , Langius‐Eklöf Ann , Kihlgren Annica , Blomberg Karin
Published: July 2016

Aims and objectives

To develop and test feasibility and acceptability of an interactive ICT platform integrated in a tablet for collecting and managing patient‐reported concerns of older adults in home care.

Background

Using different ICT applications, for example interactive tablets for self‐assessment of health and health issues based on health monitoring as well as other somatic and psychiatric monitoring systems may improve quality of life, staff and patient communication and feelings of being reassured. The European Commission hypothesises that introduction of ICT applications to the older population will enable improved health. However, evidence‐based and user‐based applications are scarce.

Design

The design is underpinned by the Medical Research Council's complex intervention evaluation framework. A mixed‐method approach was used combining interviews with older adults and healthcare professionals, and logged quantitative data.

Methods

In cooperation with a health management company, a platform operated by an interactive application for reporting and managing health‐related problems in real time was developed. Eight older adults receiving home care were recruited to test feasibility. They were equipped with the application and reported three times weekly over four weeks, and afterwards interviewed about their experiences. Three nurses caring for them were interviewed. The logged data were extracted as a coded file.

Results

The older adults reported as instructed, in total 107 reports (Mean 13). The most frequent concerns were pain, fatigue and dizziness. The older adults experienced the application as meaningful with overall positive effects as well as potential benefits for the nurses involved.

Conclusions

The overall findings in this study indicated high feasibility among older adults using the ICT platform. The study's results support further development of the platform, as well as tests in full‐scale studies and in other populations.

Relevance to clinical practice

An ICT platform increased the older adults' perception of involvement and facilitated communication between the patient and nurses.
Effects of defaunation and dietary coconut oil distillate on fermentation, digesta kinetics and methane production of Brahman heifers
Authors: Nguyen S. H. , Hegarty R. S.
Published: July 2016

A 2 × 2 factorial experiment was conducted to assess the effects of presence or absence of rumen protozoa and of dietary coconut oil distillate (COD) supplementation on rumen fermentation characteristics, digesta kinetics and methane production in Brahman heifers. Twelve Brahman heifers were selected to defaunate, with 6 being subsequently refaunated. After defaunation and refaunation, heifers were randomly allocated to COD supplement or no supplement treatments while fed an oaten chaff‐based diet. Methane production (MP; 94.17 v 104.72 g CH4/d) and methane yield [MY; 19.45 v 21.64 g CH4/kg dry matter intake (DMI)] were reduced in defaunated heifers compared with refaunated heifers when measured at 5 weeks after refaunation treatment (p < 0.01). Supplement of COD similarly reduced MP and MY (89.36 v 109.53 g/d and 18.46 v 22.63 g/kg DMI, respectively; p < 0.01), and there were no significant interactions of defaunation and COD effects on rumen fermentation or methane emissions. Concentration of total volatile fatty acid (VFA) and molar proportions of acetate, propionate and butyrate was not affected by defaunation or by COD. Microbial crude protein (MCP; g/d) outflow was increased by defaunation (p < 0.01) in the absence of COD but was unaffected by defaunation in COD‐supplemented heifers. There was a tendency towards a greater average daily gain (ADG) in defaunated heifers (p = 0.09), but COD did not increase ADG (p > 0.05). The results confirmed that defaunation and COD independently reduced enteric MP even though the reduced emissions were achieved without altering rumen fermentation VFA levels or gut digesta kinetics.
Sleep deprivation increases formation of false memory
Authors: Lo June C. , Chong Pearlynne L. H. , Ganesan Shankari , Leong Ruth L. F. , Chee Michael W. L.
Published: July 2016

Retrieving false information can have serious consequences. Sleep is important for memory, but voluntary sleep curtailment is becoming more rampant. Here, the misinformation paradigm was used to investigate false memory formation after 1 night of total sleep deprivation in healthy young adults (N = 58, mean age ± SD = 22.10 ± 1.60 years; 29 males), and 7 nights of partial sleep deprivation (5 h sleep opportunity) in these young adults and healthy adolescents (N = 54, mean age ± SD = 16.67 ± 1.03 years; 25 males). In both age groups, sleep‐deprived individuals were more likely than well‐rested persons to incorporate misleading post‐event information into their responses during memory retrieval (P < 0.050). These findings reiterate the importance of adequate sleep in optimal cognitive functioning, reveal the vulnerability of adolescents' memory during sleep curtailment, and suggest the need to assess eyewitnesses' sleep history after encountering misleading information.
Effects of Dietary Taurine on the Growth, Digestive Enzymes, and Antioxidant Capacity in Juvenile Sea Cucumber, Apostichopus japonicus
Authors: Zhao Yancui , Zhang Qin , Yuan Lei , Liu Xueqian
Published: July 2016

Taurine has been widely used as a growth‐ or health‐promoting additive in aquatic animals because of its multiple functions, while little work has been done on its effects on sea cucumbers, in spite of the occurrence of serious diseases. In this study, juvenile sea cucumbers (4.68 ± 0.04 g) were fed diets supplemented with taurine at 0% (control), 0.1, 0.25, 0.5, 1, and 2% for 8 wk. At the end of an 8‐wk feeding trial, growth performance of sea cucumbers was not significantly affected by dietary taurine (P > 0.05). However, dietary taurine significantly elevated intestinal lipase activities of sea cucumbers (P < 0.05). Intestinal amylase activity and trypsin activity in sea cucumbers did not show significant changes after animals were fed diets supplemented with taurine (P > 0.05). Dietary taurine at all five dosages significantly increased total antioxidant capacity in sea cucumbers, while superoxide dismutase activity in groups with dietary taurine at 0.25 and 0.5% was significantly higher than that of the control group (P < 0.05). Therefore, it appears that taurine could be used as a potential feed additive to confer better health of farmed sea cucumbers.
An Extension of Ausubel's Auction for Heterogeneous Discrete Goods
Authors: İnal Hakan
Published: July 2016

Ausubel's dynamic private‐values auction for heterogeneous discrete goods, Ausubel (2006), yields an efficient equilibrium outcome but it is designed for a limited class of environments. If bidders’ values for bundles of goods are not integers, then Ausubel's auction may end without allocating goods if no information on bidders’ values is available. In this paper, I extend Ausubel's auction for heterogeneous discrete goods to real‐valued quasilinear utility functions. The mechanism I propose reaches a Walrasian equilibrium price vector in finite ‘steps’ without any additional information on bidders’ values. In the extension of Ausubel's auction, truthful bidding constitutes an efficient equilibrium.
RpoS‐dependent sRNA RgsA regulates Fis and AcpP in Pseudomonas aeruginosa
Authors: Lu Pei , Wang Yifei , Zhang Yong , Hu Yangbo , Thompson Karl M. , Chen Shiyun
Published: July 2016

RgsA is a phylogenetically conserved small regulatory RNA (sRNA) in Pseudomonas species. This sRNA has been shown to be directly controlled by the major stationary phase and stress sigma factor σS (RpoS), and also indirectly regulated by the GacS/GacA two‐component system. However, the role and the regulatory targets of this sRNA remain unclear. Here, two direct regulatory targets of RgsA, the mRNAs coding for the global transcriptional regulator Fis and the acyl carrier protein AcpP, were identified in P. aeruginosa. RgsA downregulates the synthesis of Fis and AcpP by base‐pairing, and this regulation requires the RNA chaperone protein Hfq. Alignment of RgsA homologs in Pseudomonas revealed a conserved core region, which is strictly required for RgsA target recognition. Specifically, RgsA inhibits fis expression via an 11 + 11 bp RNA duplex, whereas this interaction region is not sufficient for repression and the 35 nt downstream region is also required. Interestingly, two functional start codons initiate fis mRNA translation and both are repressed by RgsA. Furthermore, deletion of rgsA significantly increased swarming motility in P. aeruginosa. Together, this study suggests a novel regulatory role of sRNA in which the versatile transcriptional regulator Fis and the stress regulator RpoS are connected by RgsA.
Anti‐inflammatory and protective effects of saffron extract in ischaemia/reperfusion‐induced acute kidney injury
Authors: Mahmoudzadeh Leila , Najafi Houshang , Ashtiyani Saeed Changizi , Yarijani Zeynab Mohamadi
Published: July 2016

Aim

Inflammation is one of the major challenges in the management of ischaemia/reperfusion (I/R)‐induced acute kidney injury. Our aim was to assess the anti‐inflammatory and protective effects of saffron extract against I/R‐induced renal disturbances.

Methods

A total of 35 male Wistar rats were randomly divided into five groups (n = 7) as sham, I/R and three groups of I/R that were pretreated with different doses of saffron extract (5 mg/kg, 10 mg/kg, or 20 mg/kg) intraperitoneally. The I/R‐induced renal inflammation was assessed by measuring leukocyte infiltration and mRNA expression levels of intercellular adhesion molecule‐1 and tumour necrotic factor‐alpha. For the assessment of oxidative stress, thiobarbituric acid reactive species and antioxidant capacity of kidneys were measured in the right kidneys. In addition, plasma creatinine and urea‐nitrogen concentrations were determined for renal functional disturbances. Statistical analysis was performed using one‐way analysis of variance using the Duncan post hoc test.

Results

The I/R increased all of the measured parameters, except for the tissue level of ferric reducing/antioxidant power, which decreased. Pretreatment with saffron extract in all doses significantly reduced the severity of these disturbances in such a way that there were no significant differences between the FRAP level and urea‐nitrogen concentrations between the sham and all three saffron extract‐treated groups. However, the saffron extract could decrease the plasma creatinine concentration, malondialdehyde level, tumour necrotic factor‐alpha and intercellular adhesion molecule‐1 expression and leukocyte infiltration in a dose‐dependent manner.

Conclusion

The present study showed anti‐inflammatory, anti‐oxidative and protective effects for the hydro‐ethanolic extract of saffron in I/R‐induced acute kidney injury.
Lactobacillus rhamnosus strain JB‐1 reverses restraint stress‐induced gut dysmotility
Authors: West C. , Wu R. Y. , Wong A. , Stanisz A. M. , Yan R. , Min K. K. , Pasyk M. , McVey Neufeld K.‐A. , Karamat M. I. , Foster J. A. , Bienenstock J. , Forsythe P. , Kunze W. A.
Published: July 2016

Background

Environmental stress affects the gut with dysmotility being a common consequence. Although a variety of microbes or molecules may prevent the dysmotility, none reverse the dysmotility.

Methods

We have used a 1 hour restraint stress mouse model to test for treatment effects of the neuroactive microbe, L. rhamnosus JB‐1™. Motility of fluid‐filled ex vivo gut segments in a perfusion organ bath was recorded by video and migrating motor complexes measured using spatiotemporal maps of diameter changes.

Key Results

Stress reduced jejunal and increased colonic propagating contractile cluster velocities and frequencies, while increasing contraction amplitudes for both. Luminal application of 10E8 cfu/mL JB‐1 restored motor complex variables to unstressed levels within minutes of application. L. salivarius or Na.acetate had no treatment effects, while Na.butyrate partially reversed stress effects on colonic frequency and amplitude. Na.propionate reversed the stress effects for jejunum and colon except on jejunal amplitude.

Conclusions & Inferences

Our findings demonstrate, for the first time, a potential for certain beneficial microbes as treatment of stress‐induced intestinal dysmotility and that the mechanism for restoration of function occurs within the intestine via a rapid drug‐like action on the enteric nervous system.
How can we deal with the GERD treatment gap?
Authors: Triadafilopoulos George , Azagury Dan
Published: July 2016

Patients experiencing heartburn and acid regurgitation despite proton pump inhibition therapy who are averse to antireflux surgery fall into what is called the gastroesophageal reflux disease (GERD) treatment gap. This gap may be potentially addressed by several endoscopic and laparoscopic techniques, including gastric bypass surgery for those patients who are obese. These novel techniques do not significantly alter the anatomy of the esophagogastric junction, minimizing short‐ and long‐term adverse effects. This review provides an overview of the assessment of patients with refractory GERD and highlights the strengths and weaknesses of these minimally invasive therapies.
Transnormativity: A New Concept and Its Validation through Documentary Film About Transgender Men
Authors: Johnson Austin H.
Published: July 2016

While prior research has called attention to how medically based, normative understandings of sex and gender place undue restrictions on transgender people's autonomy, there has yet to be an attempt to consolidate this research into a recognizable concept that is situated within existing theoretical frameworks. This article uses documentary films focused on transgender men as an empirical example to develop the concept of transnormativity. Transnormativity describes the specific framework to which transgender people's presentations and experiences of gender are held accountable. Drawing on research specific to transgender community groups, medicalization, and legal transition, I argue that transnormativity structures transgender experience, identification, and narratives into a hierarchy of legitimacy that is dependent upon medical standards. This ideology, as I show via a content analysis of documentary films, circulates in media depictions of transgender people in ways that eclipse alternative explanations of gender non‐conformity. While medical transition is a central component of many transgender people's gender trajectory, I argue in this article that the privileging of the medical model over others creates a marginalizing effect for gender‐non‐conforming people who cannot or do not wish to medically transition.
Deformation During the Electrosurgical Vessel Sealing Process
Authors: Wyatt H. L. , Pullin R. , Yang T. H. J. , Evans S. L.
Published: July 2016

Electrosurgical vessel sealing is used throughout many surgical procedures with the benefits of the device widely reported. However, there is still significant variation in the quality of the resulting seal with limited understanding as to why. This study developed a methodology to use digital image correlation to capture the sealing process and to investigate the changes occurring throughout. Porcine carotid arteries were used throughout the study, with seals created using the Gyrus G400 generator and the PKS Open Seal device (Gyrus Medical Ltd, Cardiff, United Kingdom).

The displacement across the surface of the blood vessel and the device jaws was measured, and the true maximum principal strain was computed. There was significant contraction of the tissue along the length of the blood vessel, with this occurring in pulses due to the waveform used to deliver the current. Additionally, there was a significant change in displacement between the device jaws (0.08 mm), a novel finding of the study. This change in displacement is indicative of a change in application force throughout sealing, which can have significant implications in the quality of the seal, and therefore the findings of this study can influence future device design.
Exhumation of the Dora Maira ultrahigh‐pressure unit by buoyant uprise within a low‐viscosity mantle oblique‐slip shear zone
Authors: Schmalholz Stefan M. , Schenker Filippo L.
Published: July 2016

The Brossasco‐Isasca subunit (BIU) of the Dora Maira massif is currently the only known continental crustal ultrahigh‐pressure (UHP) unit in the Western Alps. The peak pressure/temperature conditions are 3.5–4.5 GPa/~730 °C; exhumation from ~3.5 GPa to ~1 GPa occurred within 2.2 ± 1.8 Ma, but the exhumation mechanism is incompletely understood. We present a conceptual model for the buoyancy‐driven exhumation of the BIU inside a low‐viscosity, dense mantle shear zone weakened by increased strain rates due to simultaneous strike‐slip and subduction (oblique‐slip) of the European plate. Two‐dimensional thermo‐mechanical models simulate such a buoyant uprise of an ellipse inside an inclined layer. Simulations (i) show the feasibility of the conceptual model, (ii) fit the pressure/temperature/time record and (iii) constrain effective viscosities. The model is compatible with the (i) small volume of continental crustal UHP rock in the Western Alps, (ii) minor erosion during exhumation and (iii) strike‐slip deformation during the exhumation period.
Bacterial meningitis in solid organ transplant recipients: a population‐based prospective study
Authors: van Veen K.E.B. , Brouwer M.C. , van der Ende A. , van de Beek D.
Published: July 2016

Background

Solid organ transplant (SOT) recipients are at risk of infections of the central nervous system. However, the incidence and clinical course of bacterial meningitis in SOT recipients are unclear. We studied occurrence, disease course, and prognosis of bacterial meningitis in SOT recipients in the Netherlands.

Methods

All patients with a medical history of solid organ transplantation were selected from our nationwide prospective cohort study on community‐acquired bacterial meningitis in patients >16 years old, performed from March 1, 2006 to October 31, 2014. Data on patient history, symptoms and signs on admission, treatment, and outcome were collected prospectively. For transplant recipients, additional information was collected retrospectively.

Results

We identified 6 SOT recipients, all receiving renal transplants. The annual incidence of bacterial meningitis was 7‐fold higher (95% confidence interval [CI] 2.94–17.02, P < 0.001) for renal transplant recipients as compared with the general population (9.56 [95% CI 3.98–22.96] vs. 1.35 [95% CI 1.28–1.43] per 100,000 patients per year). One of the 6 patients (17%) presented with the classic presentation of bacterial meningitis (fever, neck stiffness, and change in mental status). Seizures were common, occurring in 33% of patients. Streptococcus pneumoniae and Listeria monocytogenes were identified in 2 patients each, and Escherichia coli and Pseudomonas aeruginosa were both identified once. Four of 6 patients (67%) had an unfavorable functional outcome.

Conclusion

Bacterial meningitis is a rare but devastating complication of solid organ transplantation. SOT recipients are at high risk for developing meningitis, and recognition of this condition may be difficult, owing to atypical clinical manifestation.
Leukoreduced red blood cell transfusions do not induce platelet glycoprotein antibodies in patients with sickle cell disease
Authors: Nickel Robert Sheppard , Winkler Anne M. , Horan John T. , Hendrickson Jeanne E.
Published: July 2016

BACKGROUND

Alloimmunization to red blood cell (RBC) antigens after transfusion is well described in patients with sickle cell disease (SCD). We recently demonstrated that leukocyte‐reduced RBC transfusions appeared to induce human leukocyte antigen (HLA) antibodies in some children with SCD; now, we hypothesize that residual platelets contained in transfused RBC products may lead to platelet glycoprotein antibody formation.

STUDY DESIGN AND METHODS

A cross‐sectional study was conducted among never pregnant pediatric patients with SCD who either had received many RBC transfusions or had never received any transfusions. Serum was tested for antibodies to platelet‐specific glycoproteins using a commercial enzyme immunoassay.

RESULTS

Platelet‐specific glycoprotein antibodies were found in 12 of 90 patients (13%) in the transfused group versus 5 of 24 patients (21%) in the never transfused group (p = 0.35). The prevalence of antibodies as well as the median standardized optical density for these two groups was not significantly different for any of the studied platelet glycoprotein antigens. There was no association with the presence of platelet‐specific glycoprotein antibodies with either RBC or HLA antibodies.

CONCLUSIONS

Leukocyte‐reduced RBC transfusions do not appear to induce platelet‐specific glycoprotein antibodies. The positive platelet‐specific glycoprotein antibody results from this study may represent platelet autoantibodies, platelet alloantibodies, or false‐positive reactions. A better understanding of the immunobiology of patients with SCD at baseline and after blood product exposure may help improve future transfusion and transplantation.
Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer
Authors: Tie Jeanne , Wang Yuxuan , Tomasetti Cristian , Li Lu , Springer Simeon , Kinde Isaac , Silliman Natalie , Tacey Mark , Wong Hui-Li , Christie Michael , Kosmider Suzanne , Skinner Iain , Wong Rachel , Steel Malcolm , Tran Ben , Desai Jayesh , Jones Ian , Haydon Andrew , Hayes Theresa , Price Tim J. , Strausberg Robert L. , Diaz Luis A. , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Gibbs Peter
Published: July 2016

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease.
Small cell lung cancer: Time to revisit DNA-damaging chemotherapy
Authors: Thomas Anish , Pommier Yves
Published: July 2016

Rational use of DNA-damaging chemotherapy, with new combinations to heighten DNA replication stress, could improve outcomes in small cell lung cancer.
The future is unsupervised
Authors: Greene Casey S.
Published: July 2016

A new algorithm infers shared biology behind detected gene expression levels.
Effect of the β-Lactamase Inhibitor Vaborbactam Combined with Meropenem against Serine Carbapenemase-Producing Enterobacteriaceae
Authors: Castanheira Mariana , Rhomberg Paul R. , Flamm Robert K. , Jones Ronald N.
Published: July 2016

Klebsiella pneumoniae
carbapenemase (KPC)-producing isolates have become increasingly prevalent worldwide, and these organisms are often multidrug resistant, limiting the therapeutic options available for treating infections. We evaluated the activity of meropenem combined with the serine β-lactamase inhibitor vaborbactam (formerly RPX7009) against 315 serine carbapenemase-producing
Enterobacteriaceae
(CPE) isolates by use of checkerboard-designed panels to assess the optimal inhibitor concentration (range tested, 0.5 to 32 μg/ml). Overall, meropenem alone (MIC
50
and MIC
90
, 16 and >64 μg/ml, respectively) inhibited only 2.2% of the isolates at ≤1 μg/ml (the CLSI susceptibility breakpoint) and 7.3% of the isolates at ≤2 μg/ml (the EUCAST breakpoint). Vaborbactam restored meropenem activity for 72.7 to 98.1% of CPE isolates at ≤2 μg/ml, and maximum potentiation was achieved with fixed concentrations of ≥8 μg/ml of the inhibitor (≥96.5% of isolates were inhibited at ≤2 μg/ml of meropenem-vaborbactam). Meropenem-vaborbactam with a fixed concentration of 8 μg/ml of the inhibitor (MIC
50
, ≤0.06 μg/ml for all organisms) inhibited 93.7% of the CPE isolates displaying elevated meropenem MICs at ≤1 μg/ml. Meropenem-vaborbactam MICs were elevated for isolates producing metallo-β-lactamases (MIC, 16 to >64 μg/ml) or displaying decreased expression of OmpK37 and/or elevated expression of the AcrAB-TolC efflux system (MIC, 16 μg/ml). Vaborbactam showed no antibacterial activity alone (all MICs, >64 μg/ml). Meropenem-vaborbactam appears to be a good candidate for further development and it could increase the options for treatment of serious infections caused by carbapenemase-producing pathogens.
The Role of Signaling via Aqueous Pore Formation in Resistance Responses to Amphotericin B
Authors: Cohen B. Eleazar
Published: July 2016

Drug resistance studies have played an important role in the validation of antibiotic targets. In the case of the polyene antibiotic amphotericin B (AmB), such studies have demonstrated the essential role that depletion of ergosterol plays in the development of AmB-resistant (AmB-R) organisms. However, AmB-R strains also occur in fungi and parasitic protozoa that maintain a normal level of ergosterol at the plasma membrane. Here, I review evidence that shows not only that there is increased protection against the deleterious consequences of AmB-induced ion leakage across the membrane in these resistant pathogens but also that a set of events are activated that block the cell signaling responses that trigger the oxidative damage produced by the antibiotic. Such signaling events appear to be the consequence of a membrane-thinning effect that is exerted upon lipid-anchored Ras proteins by the aqueous pores formed by AmB. A similar membrane disturbance effect may also explain the activity of AmB on mammalian cells containing Toll-like receptors. These resistance mechanisms expand our current understanding of the role that the formation of AmB aqueous pores plays in triggering signal transduction responses in both pathogens and host immune cells.
A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus Activity
In Vitro
Authors: Jones Jeremy C. , Marathe Bindumadhav M. , Lerner Christian , Kreis Lukas , Gasser Rodolfo , Pascua Philippe Noriel Q. , Najera Isabel , Govorkova Elena A.
Published: July 2016

Antiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC
50
s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiple
in vitro
assays, supporting its further characterization and development as a potential antiviral agent for treating influenza.
Interspecies Dissemination of a Mobilizable Plasmid Harboring
bla
IMP-19
and the Possibility of Horizontal Gene Transfer in a Single Patient
Authors: Yamamoto Masaki , Matsumura Yasufumi , Gomi Ryota , Matsuda Tomonari , Tanaka Michio , Nagao Miki , Takakura Shunji , Uemoto Shinji , Ichiyama Satoshi
Published: July 2016

Carbapenemase-producing Gram-negative bacilli have been a global concern over the past 2 decades because these organisms can cause severe infections with high mortality rates. Carbapenemase genes are often carried by mobile genetic elements, and resistance plasmids can be transferred through conjugation. We conducted whole-genome sequencing (WGS) to demonstrate that the same plasmid harboring a metallo-β-lactamase gene was detected in two different species isolated from a single patient. Metallo-β-lactamase-producing
Achromobacter xylosoxidans
(KUN4507), non-metallo-β-lactamase-producing
Klebsiella pneumoniae
(KUN4843), and metallo-β-lactamase-producing
K. pneumoniae
(KUN5033) were sequentially isolated from a single patient and then analyzed in this study. Antimicrobial susceptibility testing, molecular typing (pulsed-field gel electrophoresis and multilocus sequence typing), and conjugation analyses were performed by conventional methods. Phylogenetic and molecular clock analysis of
K. pneumoniae
isolates were performed with WGS, and the nucleotide sequences of plasmids detected from these isolates were determined using WGS. Conventional molecular typing revealed that KUN4843 and KUN5033 were identical, whereas the phylogenetic tree analysis revealed a slight difference. These two isolates were separated from the most recent common ancestor 0.74 years before they were isolated. The same resistance plasmid harboring
bla
IMP-19
was detected in metallo-β-lactamase-producing
A. xylosoxidans
and
K. pneumoniae
. Although this plasmid was not self-transferable, the conjugation of this plasmid from
A. xylosoxidans
to non-metallo-β-lactamase-producing
K. pneumoniae
was successfully performed. The susceptibility patterns for metallo-β-lactamase-producing
K. pneumoniae
and the transconjugant were similar. These findings supported the possibility of the horizontal transfer of plasmid-borne
bla
IMP-19
from
A. xylosoxidans
to
K. pneumoniae
in a single patient.
Beneficial Effects of Sodium Phenylbutyrate Administration during Infection with Salmonella enterica Serovar Typhimurium
Authors: Jellbauer Stefan , Perez Lopez Araceli , Behnsen Judith , Gao Nina , Nguyen Thao , Murphy Clodagh , Edwards Robert A. , Raffatellu Manuela
Published: July 2016

Sodium phenylbutyrate (PBA) is a derivative of the short-chain fatty acid butyrate and is approved for treatment of urea cycle disorders and progressive familial intrahepatic cholestasis type 2. Previously known functions include histone deacetylase inhibitor, endoplasmic reticulum stress inhibitor, ammonia sink, and chemical chaperone. Here, we show that PBA has a previously undiscovered protective role in host mucosal defense during infection. Administration of PBA to Taconic mice resulted in the increase of intestinal
Lactobacillales
and segmented filamentous bacteria (SFB), as well as an increase of interleukin 17 (IL-17) production by intestinal cells. This effect was not observed in Jackson Laboratory mice, which are not colonized with SFB. Because previous studies showed that IL-17 plays a protective role during infection with mucosal pathogens, we hypothesized that Taconic mice treated with PBA would be more resistant to infection with
Salmonella enterica
serovar Typhimurium (
S
. Typhimurium). By using the streptomycin-treated mouse model, we found that Taconic mice treated with PBA exhibited significantly lower
S
. Typhimurium intestinal colonization and dissemination to the reticuloendothelial system, as well as lower levels of inflammation. The lower levels of
S
. Typhimurium gut colonization and intestinal inflammation were not observed in Jackson Laboratory mice. Although PBA had no direct effect on bacterial replication, its administration reduced
S
. Typhimurium epithelial cell invasion and lowered the induction of the proinflammatory cytokine IL-23 in macrophage-like cells. These effects likely contributed to the better outcome of infection in PBA-treated mice. Overall, our results suggest that PBA induces changes in the microbiota and in the mucosal immune response that can be beneficial to the host during infection with
S
. Typhimurium and possibly other enteric pathogens.
CagA Phosphorylation in Helicobacter pylori-Infected B Cells Is Mediated by the Nonreceptor Tyrosine Kinases of the Src and Abl Families
Authors: Krisch Linda M. , Posselt Gernot , Hammerl Peter , Wessler Silja
Published: July 2016

CagA is one of the most important virulence factors of the human pathogen
Helicobacter pylori
. CagA expression can be associated with the induction of severe gastric disorders such as gastritis, ulceration, gastric cancer, or mucosa-associated lymphoid tissue (MALT) lymphoma. After translocation through a type IV secretion system into epithelial cells, CagA is tyrosine phosphorylated by kinases of the Src and Abl families, leading to drastic cell elongation and motility. While the functional role of CagA in epithelial cells is well investigated, knowledge about CagA phosphorylation and its associated signal transduction pathways in B cells is only marginal. Here, we established the B cell line MEC1 derived from a B cell chronic lymphocytic leukemia (B-CLL) patient as a new infection model to study the signal transduction in B cells controlled by
H. pylori
. We observed that CagA was rapidly injected, strongly tyrosine phosphorylated, and cleaved into a 100-kDa N-terminal and a 40-kDa C-terminal fragment. To identify upstream signal transduction pathways of CagA phosphorylation in MEC1 cells, pharmacological inhibitors were employed to specifically target Src and Abl kinases. We observed that CagA phosphorylation was strongly inhibited upon treatment with an Src inhibitor and slightly diminished when the Abl kinase inhibitor imatinib mesylate (Gleevec) was applied. The addition of dasatinib to block c-Abl and Src kinases led to a complete loss of CagA phosphorylation. In conclusion, these results demonstrate an important role for Src and Abl tyrosine kinases in CagA phosphorylation in B cells, which represent druggable targets in
H. pylori
-mediated gastric MALT lymphoma.
The ChrSA and HrrSA Two-Component Systems Are Required for Transcriptional Regulation of the
hemA
Promoter in Corynebacterium diphtheriae
Authors: Burgos Jonathan M. , Schmitt Michael P.
Published: July 2016

Corynebacterium diphtheriae
utilizes heme and hemoglobin (Hb) as iron sources for growth in low-iron environments. In
C. diphtheriae
, the two-component signal transduction systems (TCSs) ChrSA and HrrSA are responsive to Hb levels and regulate the transcription of promoters for
hmuO
,
hrtAB
, and
hemA
. ChrSA and HrrSA activate transcription at the
hmuO
promoter and repress transcription at
hemA
in an Hb-dependent manner. In this study, we show that HrrSA is the predominant repressor at
hemA
and that its activity results in transcriptional repression in the presence and absence of Hb, whereas repression of
hemA
by ChrSA is primarily responsive to Hb. DNA binding studies showed that both ChrA and HrrA bind to the
hemA
promoter region at virtually identical sequences. ChrA binding was enhanced by phosphorylation, while binding to DNA by HrrA was independent of its phosphorylation state. ChrA and HrrA are phosphorylated
in vitro
by the sensor kinase ChrS, whereas no kinase activity was observed with HrrS
in vitro
. Phosphorylated ChrA was not observed
in vivo
, even in the presence of Hb, which is likely due to the instability of the phosphate moiety on ChrA. However, phosphorylation of HrrA was observed
in vivo
regardless of the presence of the Hb inducer, and genetic analysis indicates that ChrS is responsible for most of the phosphorylation of HrrA
in vivo
. Phosphorylation studies strongly suggest that HrrS functions primarily as a phosphatase and has only minimal kinase activity. These findings collectively show a complex mechanism of regulation at the
hemA
promoter, where both two-component systems act in concert to optimize expression of heme biosynthetic enzymes.

IMPORTANCE
Understanding the mechanism by which two-component signal transduction systems function to respond to environmental stimuli is critical to the study of bacterial pathogenesis. The current study expands on the previous analyses of the ChrSA and HrrSA TCSs in the human pathogen
C. diphtheriae
. The findings here underscore the complex interactions between the ChrSA and HrrSA systems in the regulation of the
hemA
promoter and demonstrate how the two systems complement one another to refine and control transcription in the presence and absence of Hb.
Mutations in the Plasmodium falciparum Cyclic Amine Resistance Locus (PfCARL) Confer Multidrug Resistance
Authors: LaMonte Gregory , Lim Michelle Yi-Xiu , Wree Melanie , Reimer Christin , Nachon Marie , Corey Victoria , Gedeck Peter , Plouffe David , Du Alan , Figueroa Nelissa , Yeung Bryan , Bifani Pablo , Winzeler Elizabeth A.
Published: July 2016

Mutations in the
Plasmodium falciparum
cyclic amine resistance locus (PfCARL) are associated with parasite resistance to the imidazolopiperazines, a potent class of novel antimalarial compounds that display both prophylactic and transmission-blocking activity, in addition to activity against blood-stage parasites. Here, we show that
pfcarl
encodes a protein, with a predicted molecular weight of 153 kDa, that localizes to the
cis
-Golgi apparatus of the parasite in both asexual and sexual blood stages. Utilizing clustered regularly interspaced short palindromic repeat (CRISPR)-mediated gene introduction of 5 variants (L830V, S1076N/I, V1103L, and I1139K), we demonstrate that mutations in
pfcarl
are sufficient to generate resistance against the imidazolopiperazines in both asexual and sexual blood-stage parasites. We further determined that the mutant PfCARL protein confers resistance to several structurally unrelated compounds. These data suggest that PfCARL modulates the levels of small-molecule inhibitors that affect Golgi-related processes, such as protein sorting or membrane trafficking, and is therefore an important mechanism of resistance in malaria parasites.

IMPORTANCE
Several previous
in vitro
evolution studies have implicated the
Plasmodium falciparum
cyclic amine resistance locus (PfCARL) as a potential target of imidazolopiperazines, potent antimalarial compounds with broad activity against different parasite life cycle stages. Given that the imidazolopiperazines are currently being tested in clinical trials, understanding their mechanism of resistance and the cellular processes involved will allow more effective clinical usage.
After All, Only Millions?
Authors: Amann Rudolf , Rosselló-Móra Ramon
Published: July 2016

An update on the census of species of
Archaea
and
Bacteria
published recently in mBio (P. D. Schloss, R. A. Girard, T. Martin, J. Edwards, and J. C. Thrash, mBio 7:e00201-16, 2016,
http://dx.doi.org/10.1128/mBio.00201-16
) showed again that, despite ever-increasing sequencing efforts, the PCR-based retrieval of 16S rRNA genes is approaching saturation. On average, 95% of the genes analyzed today are identical to those present in public databases, with rarefaction analysis indicating that about one-third of the bacterial and archaeal diversity has already been covered. Therefore, despite estimates of up to 10
12
microbial species, the option should be considered that the census of
Archaea
and
Bacteria
on planet Earth might yield only millions of species after all.