bluuebunny/crossref_metadata_2025 huggingface dataset:
Prospective evaluation of integrated device diagnostics for heart failure management: results of the TRIAGE‐HF study
Authors: Virani Sean A. , Sharma Vinod , McCann Mary , Koehler Jodi , Tsang Bernice , Zieroth Shelley
Published: June 2018

Aims

The primary aim of the TRIAGE‐HF trial was to correlate cardiac implantable electronic device‐generated heart failure risk status (HFRS) with signs, symptoms, and patient behaviours classically associated with worsening heart failure (HF).

Methods and results

TRIAGE‐HF enrolled 100 subjects with systolic HF implanted with a Medtronic high‐performance device and followed up at three Canadian HF centres. Study follow‐up was up to 8 months. The HFRS assigned each subject's overall risk of HF hospitalization in the next 30 days and also highlighted abnormal device parameters contributing to a patient's risk status at the time of remote data transmission. Subjects with a high HFRS were contacted by telephone to assess symptoms, and compliance with prescribed therapies, nutrition, and exercise. Clinician‐assessed risk and HFRS‐calculated risk were correlated at both study baseline and exit. Twenty‐four high HFRS occurrences were observed among 100 subjects. Device parameters associated with increased risk of HF hospitalization included OptiVol index (n = 20), followed by low patient activity (n = 18) and elevated night heart rate (n = 12). High HFRS was associated with symptoms of worsening HF in 63% of cases (n = 15) increasing to 83% of cases (n = 20) when non‐compliance with pharmacological therapies and lifestyle was considered.

Conclusions

TRIAGE‐HF is the first study to provide prospective data on the distribution of abnormal device parameters contributing to high HFRS. High HFRS has good predictive accuracy for patient‐reported signs, symptoms, and behaviours associated with worsening HF status. As such, HFRS may be a useful tool for ambulatory HF monitoring to improve both patient‐centred and health system level outcomes.
IFN‐γ protects from apoptotic neutrophil‐mediated tissue injury during acute Listeria monocytogenes infection
Authors: Wang Guan , Lin Ang , Han Qiuju , Zhao Huajun , Tian Zhigang , Zhang Jian
Published: June 2018

Listeria monocytogenes (LM) is a foodborne Gram‐positive intracellular pathogen that can cause listeriosis in humans and animals. Although phagocytes are known to be involved in the response to this infection, the role of neutrophils is not entirely clear. Here, we have demonstrated that soon after LM infection, a large number of IFN‐γ‐producing neutrophils quickly accumulated in the spleen, blood, and peritoneal cavity. Both in vivo and in vitro experiments demonstrated that neutrophils were an important source of IFN‐γ. IFN‐γ played a critical protective role against acute LM infection, as demonstrated by the poor survival of Ifng−/− mice. Moreover, IFN‐γ promoted bacterial clearance by the neutrophils, thereby inhibiting LM‐induced neutrophil apoptosis and spleen damage. In addition to this, IFN‐γ could effectively drive macrophage‐mediated phagocytosis of apoptotic neutrophils, which was accompanied with TGF‐β secretion and was involved in protection against tissue injury. Importantly, by phagocytizing apoptotic neutrophils, macrophages obtained myeloperoxidase, an important bactericidal molecule only produced by neutrophils, which further promoted the antibacterial activity of macrophages. These findings demonstrate that neutrophils are an important source of IFN‐γ at the early stage of LM infection, which is characterized by both LM elimination and tissue‐protective effects.
An Electrocatalyst for a Hydrogen Evolution Reaction in an Alkaline Medium: Three‐Dimensional Graphene Supported CeO2 Hollow Microspheres
Authors: Liu Miaomiao , Ji Zhenyuan , Shen Xiaoping , Zhou Hu , Zhu Jun , Xie Xulan , Song Chunsen , Miao Xuli , Kong Lirong , Zhu Guoxing
Published: June 2018

Transition metal oxides (TMO) are promising candidates for low‐cost and high‐efficiency catalysts for the hydrogen evolution reaction (HER). However, the low conductivity and severe agglomeration of catalyst particles hinder their practical application. Herein, we report an effective HER electrocatalyst of 3D‐rGO‐CeO2 with three‐dimensional reduced graphene oxide (3D‐rGO) decorated with CeO2 hollow microspheres through a hydrothermal self‐assembly approach. It is shown that the CeO2 hollow microspheres with an average size of ca. 680 nm are uniformly encapsulated within the porous structure of 3D‐rGO. Compared with bare CeO2 hollow microspheres, the 3D‐rGO‐CeO2 composite exhibits remarkably enhanced electrocatalytic activity for HER with a relatively low onset overpotential of 192 mV, a smaller overpotential of 0.34 V at the current density of 10 mA cm–2, and a modest Tafel slope of 112.8 mV decade–1 in a 1 m KOH solution. The enhanced performance of 3D‐rGO‐CeO2 can be ascribed to the introduction of 3D rGO in the composite, which provides a highly conductive network for rapid charge‐carrier transmission, and rich porous structures for the easy access of the electrolyte to the catalyst during the HER process.
Selective Catalytic Hydration of Alkynes in the Presence of Au‐Cavitands: A Study in Structure–Activity Relationships
Authors: Inoue Mami , Ugawa Katto , Maruyama Tomoyuki , Iwasawa Tetsuo
Published: June 2018

The effects of the catalytic cavities in gold‐functionalized cavitands in the hydration of internal alkynes have been studied. Variations on cavitand structures revealed the importance of two features that were studied: (1) flanking aromatic rings, and (2) an adjacent P=O moiety. The di‐quinoxaline‐spanned resorcin[4]arene system provides a well‐defined compartment, in which a cationic Au ion activates an internal alkyne for conversion into a ketone by delivery of water that has also been activated, this time by a P=O moiety. We synthesized four variations on our parent cavitand. Variations of the cavitand walls include replacement of quinoxaline components with pyrazine or methylene units. Variation of the P=O center was accomplished with methylene or quinoxaline moieties. All variants displayed lower catalytic activity or selectivity, allowing us to confirm the significance both of an internal cavity and of an activation site for water.
Impact of medial versus lateral knee pain on deep tissue hyperalgesia and muscle strength
Authors: Oda S. , Izumi M. , Aso K. , Ikeuchi M.
Published: June 2018

Background

Accumulating evidence indicates that knee pain gives rise to sensory and motor alterations, however, whether different profile of knee pain causes different alterations has not been investigated. The purpose of this experimental study is to clarify characteristics of medial and lateral knee pain and its potential for modulating sensory and motor function in humans.

Methods

Fourteen healthy men were included. Medial knee pain (MP) was induced by injection of hypertonic saline (0.5 mL) into the tibial insertion of the medial collateral ligament. For comparison, lateral knee pain (LP) was induced by injection of hypertonic saline identically into the iliotibial tract. Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a continuous electronic visual analogue scale (VAS). Before, during and after the painful state, pressure pain thresholds from the knee (PPTs), maximal isometric muscle strength of the quadriceps and grip power were assessed bilaterally.

Results

MP demonstrated significantly higher VAS scores than LP and compared with control. PPTs decreased on medial and lateral knee in MP but only on the lateral knee in LP. Quadriceps muscle strength and grip power reduced bilaterally in both models, however, MP caused significantly greater reduction of ipsilateral quadriceps strength compared with LP.

Conclusion

Medial knee pain has a greater impact on deep tissue hyperalgesia and reduction of the muscle strength compared with lateral knee pain. This is a novel finding that should be taken into consideration in a treatment strategy for painful knee patients.

Significance

The experimental medial knee pain model demonstrated higher pain intensity, more localized pain distribution, widespread deep tissue hyperalgesia and more severe inhibition of muscle strength compared with the lateral knee pain model.
Mutation in Nav1.7 causes high olfactory sensitivity
Authors: Haehner A. , Hummel T. , Heinritz W. , Krueger S. , Meinhardt M. , Whitcroft K. L. , Sabatowski R. , Gossrau G.
Published: June 2018

Mutations in the sodium‐channel Nav1.7, encoded by the gene SCN9A, are known to cause pain disorders. In particular, gain‐of‐function missense mutations in Nav1.7 have been shown to be causal in primary erythromelalgia. We present a patient with erythromelalgia, pain attacks and hyperosmia with a mutation within the sodium‐channel gene SCN9A. A 50‐year‐old woman presented with burning pain in both feet and abdominal pain attacks developed over the course of 10 years. Furthermore, this patient experienced a hypersensitivity for odours. Clinical investigation as well as serum/cerebrospinal fluid laboratory findings and electrophysiological testing were unremarkable. Olfactory testing showed high olfactory acuity for all screened modalities and good intranasal sensitivity. Furthermore, quantitative sensory testing within the trigeminal area revealed very low thresholds for thermal, tactile and pain detection. In addition, quantitative sensory testing at the lower legs showed hyperalgesia and, as the disease progresses, thermal sensory function loss. Skin biopsies of the proximal and distal lower limbs revealed reduced epidermal nerve fibre density indicating small fibre neuropathy. Genetic analysis of the SCN9A gene demonstrated a heterozygous mutation in Exon 20 – c.3734A>G (p.N1245S). Treatment with clinically available sodium‐channel inhibitors did not result in significant pain relief. Local application of the sodium‐channel blocker ambroxol however, reduced pain intensity. Continuous odour exposure stabilised mood and induced a short‐term pain relief. This clinical note illustrates the course of middle‐age onset erythromelalgia and points to clinical findings related to a likely pathogenic missense mutation affecting the sodium‐channel Nav1.7.

Significance

This case report illustrates the course of middle‐age onset erythromelalgia with presumed gain‐of‐function in olfactory and pain sensation associated with a Nav1.7 channel mutation.
The role of psychological flexibility in relation to suicidal thinking in chronic pain
Authors: McCracken L.M. , Patel S. , Scott W.
Published: June 2018

Background

Suicidal thinking (ST) is common in people with chronic pain. It is relevant as it can be associated with suicidal attempts, and typically reflects significant suffering. While little is known about the psychological processes that contribute to ST, current psychological models, such as the Psychological Flexibility (PF) model, could help guide further investigation. This study investigates relations between ST and components of PF in chronic pain.

Methods

Participants were 424 adults attending treatment for chronic pain in the UK. Included in measures administered before treatment were standardized measures of depression, pain, pain‐related interference, and measures of PF, including acceptance, cognitive defusion, committed action, and self‐as‐context. An item from the measure of depression was used to reflect ST.

Results

A large proportion of the sample reported ST, 45.7%. ST was uncorrelated with participant background characteristic, medications taken, or pain intensity. However, it was correlated with the presence of widespread pain, pain‐related interference, and depression. Each component of PF was found to be significantly negatively associated with ST, as predicted. General acceptance correlated with ST at a level equal to that achieved by the depression score. In adjusted multivariate logistic regression general acceptance and committed action remained significantly uniquely associated with it.

Conclusion

This preliminary study suggests for the first time that components of PF are associated with part of a pattern of suicidal behaviour in people with chronic pain. They may be relevant for reducing avoidance in general and providing more positive behavioural options.

Significance

This study provides evidence that components of psychological flexibility are associated with a reduced frequency of suicidal thinking in people with chronic pain. Treatments targeting psychological flexibility may help mitigate the impact of chronic pain on suicidal thinking.
Compensation of the baseline temperature fluctuations for autonomous CE–C4D instrument working in harsh environments
Authors: Drevinskas Tomas , Telksnys Laimutis , Maruška Audrius , Gorbatsova Jelena , Kaljurand Mihkel
Published: June 2018

One of the main problems of the remote complex sample analysis instrumentation is that such systems are susceptible to temperature fluctuations. Temperature regulation is energetically ineffective, and it is not used in most of the field portable analytical systems. Separations performed in a changing temperature environment provide electropherograms with considerable baseline fluctuations, resulting in significant errors in detection and integration of the peaks. This paper describes electropherogram baseline compensation that is suitable for the capillary electrophoresis–contactless conductivity detection analytical method. The baseline compensation utilizes linear or polynomial data processing methods, and can be programmed in‐line using simple microcontroller, or on‐line and off‐line in data acquisition software. This method is targeted for field portable and autonomous analytical systems that are utilized in a fluctuating environment.
Optimization of a capillary zone electrophoresis–contactless conductivity detection method for the determination of nisin
Authors: Drevinskas Tomas , Stankevičius Mantas , Bimbiraitė‐Survilienė Kristina , Naujokaitytė Gintarė , Kaškonienė Vilma , Kondrotienė Kristina , Šernienė Loreta , Kornyšova Olga , Malakauskas Mindaugas , Maruška Audrius
Published: June 2018

Determination of natural preservatives using electrophoretic or chromatographic techniques in fermented milk products is a complex task due to the following reasons: (i) the concentrations of the analytes can be below the detection limits, (ii) complex matrix and comigrating/coeluting compounds in the sample can interfere with the analytes of the interest, (iii) low recovery of the analytes, and (iv) the necessity of complex sample preparation. The aim of this study was to apply capillary zone electrophoresis coupled with contactless conductivity detection for the separation and determination of nisin in fermented milk products. In this work, separation and determination of natural preservative–nisin in fermented milk products is described. Optimized conditions using capillary zone electrophoresis coupled with capacitance‐to‐digital technology based contactless conductivity detector and data conditioning, which filter the noise of the electropherogram adaptively to the peak migration time, allowed precise, accurate, sensitive (limit of quantification: 0.02 μg/mL), and most importantly requiring very minute sample preparation, determination of nisin. Sample preparation includes following steps: (i) extraction/dilution and (ii) centrifugation. This method was applied for the determination of nisin in real samples, i.e. fermented milk products. The values of different nisin forms were ranging from 0.056 ± 0.003 μg/mL to 9.307 ± 0.437 μg/g.
A discontinuous Galerkin residual‐based variational multiscale method for modeling subgrid‐scale behavior of the viscous Burgers equation
Authors: Stoter Stein K.F. , Turteltaub Sergio R. , Hulshoff Steven J. , Schillinger Dominik
Published: June 2018

We initiate the study of the discontinuous Galerkin residual‐based variational multiscale (DG‐RVMS) method for incorporating subgrid‐scale behavior into the finite element solution of hyperbolic problems. We use the one‐dimensional viscous Burgers equation as a model problem, as its energy dissipation mechanism is analogous to that of turbulent flows. We first develop the DG‐RVMS formulation for a general class of nonlinear hyperbolic problems with a diffusion term, based on the decomposition of the true solution into discontinuous coarse‐scale and fine‐scale components. In contrast to existing continuous variational multiscale methods, the DG‐RVMS formulation leads to additional fine‐scale element interface terms. For the Burgers equation, we devise suitable models for all fine‐scale terms that do not use ad hoc devices such as eddy viscosities but instead directly follow from the nature of the fine‐scale solution. In comparison to single‐scale discontinuous Galerkin methods, the resulting DG‐RVMS formulation significantly reduces the energy error of the Burgers solution, demonstrating its ability to incorporate subgrid‐scale behavior in the discrete coarse‐scale system.
Effect of different concentrations of pulverized mesocarp of Citrus paradisi Macf on the morphology and glass transition temperature of spray‐dried lemon juice powder
Authors: Alcantara Marte Yanilka , Ros Berruezo Gaspar , Alcantara Marte Yulisa , Escotto Tejada Andrea
Published: June 2018

The aim of this research was to evaluate the effect of different concentrations of pulverized mesocarp of Citrus paradisi Macf as a drying aid, on morphology, particle size and glass transition temperature of spray‐dried lemon juice powder. Five concentrations of grapefruit mesocarp (0.4%, 0.8%, 1.2%, 1.6% and 2.0% (w/w)) and maltodextrin DE 10 (1.2%, w/w) were evaluated as encapsulant agents. The obtained data were evaluated by one‐way ANOVA using Statistix version 8.0. For the means separation, the Tukey's test was applied with a 95% reliability. The morphology of the particles was described. According to the results, by applying different levels of coating agent in lemon juices, powder particles with different sizes (from 3.07 to 6.20 μm) and shapes (spherical, irregular and shrunken or reduced) are obtained; however, their glass transition temperature is not modified, finding values between 37.43 and 38.64°C.
Cervical necrotizing fasciitis: Systematic review and analysis of 1235 reported cases from the literature
Authors: Gunaratne Dakshika A. , Tseros Evan A. , Hasan Zubair , Kudpaje Akshay S. , Suruliraj Anand , Smith Mark C. , Riffat Faruque , Palme Carsten E.
Published: June 2018

Background

Cervical necrotizing fasciitis is a progressive soft tissue infection with significant morbidity and mortality.

Methods

A case review of cervical necrotizing fasciitis managed at our institution (2007‐2017) and a systematic review of PubMed, MEDLINE, and EMBASE databases using the algorithm “(cervical OR neck) AND necrotizing fasciitis.”

Results

There were 1235 cases from 207 articles which were included in our clinical review. Mean age for cervical necrotizing fasciitis was 49.1 years (64.23% men). Etiology was odontogenic (47.04%), pharyngolaryngeal (28.34%), or tonsillar/peritonsillar (6.07%). There were 2 ± 0.98 organisms identified per patient; streptococci (61.22%), staphylococci (18.09%), and prevotella (10.87%). There were 2.5 ± 3.22 surgical debridements undertaken. Descending necrotizing mediastinitis occurred in 31.56% of patients. Mean length of stay in the hospital was 29.28 days and overall mortality was 13.36%.

Conclusion

Physicians and surgeons must be vigilant of the diagnosis of cervical necrotizing fasciitis as early clinical findings may be subtle and prompt identification to facilitate aggressive intervention is required to preclude catastrophic local and systemic morbidity and mortality.
Accuracy of the HPV status site‐specific factor 10 (SSF‐10) variable for patients with oropharyngeal cancers in the Iowa Cancer Registry, 2010‐2014
Authors: Kahl Amanda R. , Charlton Mary E. , Pagedar Nitin A. , Sperry Steven M. , Matt Bobbi , Platz Charles , Lynch Charles F.
Published: June 2018

Background

Surveillance, Epidemiology, and End Results Cancer Registries (SEER) began collecting human papillomavirus (HPV) status for upper aerodigestive tract cancers in 2010. However, classification of p16‐testing was not included in the Collaborative Stage coding guidelines, potentially leading to inconsistent coding.

Methods

The HPV values for Iowa patients with oropharyngeal cancers (n = 824) were recoded based on modified guidelines that included p16 test results, and compared with the original guidelines.

Results

Forty percent of patients were recoded to a different value, and the HPV testing rate increased from 45% to 55%; 56% received p16‐testing only. Of those originally coded as HPV‐type 16 (n = 187), 89% were recoded to HPV‐not otherwise specified (NOS). When comparing high‐level positive/negative/not done categories, original coding captured 81% of patients with HPV‐positive cancers.

Conclusion

p16 was the most common HPV test but was inconsistently coded as HPV‐testing. p16‐positivity was also erroneously equated with HPV‐type 16. Adding a separate p16 variable would improve consistency and accuracy of HPV coding.
Association between diffuse lymphocytic infiltration and papillary thyroid cancer aggressiveness according to the presence of thyroid peroxidase antibody and BRAFV600E mutation
Authors: Lee Young Ki , Park Kyeong Hye , Park Se Hee , Kim Kwang Joon , Shin Dong Yeob , Nam Kee Hyun , Chung Woong Youn , Lee Eun Jig
Published: June 2018

Background

Diffuse lymphocytic infiltration (DLI) is frequently found with papillary thyroid cancer (PTC), so there has been long interest in how it affects the characteristics of PTC. This purpose of this study was to define the association between DLI and PTC aggressiveness according to thyroperoxidase antibody (TPOAb) and B‐type Raf (BRAF)V600E mutation positivity.

Methods

There were 1879 patients with PTC who underwent surgery and were enrolled in this study. Clinicopathologic characteristics were compared between groups according to the presence of DLI and TPOAb. Multiple logistic regression analysis was conducted to assess odds ratio (OR) for each dependent variable (BRAFV600E mutation, tumor size >1.0 cm, multifocality, extrathyroidal extension, and lymph node metastasis) of each group according to the presence of DLI and TPOAb, with the group with neither DLI or TPOAb (DLI‐negative TPOAb‐negative PTC) as the reference.

Results

The DLI‐positive PTC showed more frequent multifocality and less frequent BRAFV600E mutation than DLI‐negative PTC. Among patients with DLI‐positive PTC, extrathyroidal extension and BRAFV600E mutation was less frequent when serum TPOAb was positive. In multiple logistic regressions, DLI‐positive TPOAb‐positive PTC showed a high OR for multifocality (1.410; P = .017), but low ORs for BRAFV600E mutation (0.521; P < .001) and extrathyroidal extension (0.691; P = .008). The patients with DLI‐positive TPOAb‐positive PTCs showed a high OR for multifocality (1.588; P = .002), and high ORs for tumor size >1.0 cm (2.205; P = .019) and lymph node metastasis (2.005; P = .032) in subgroup analyses of PTC with wild‐type BRAF. The DLI‐negative TPOAb‐positive group was not associated with any tumor aggressiveness‐related variables.

Conclusion

Although DLI was associated with multifocality regardless of TPOAb positivity, it was associated with an indolent feature when TPOAb was positive but with aggressive features in PTC with wild‐type BRAF when TPOAb was negative. The TPOAb and BRAF status may help to define the clinical implication of lymphocytic infiltration found with PTC.
Systematic review of sentinel lymph node biopsy in Merkel cell carcinoma of the head and neck
Authors: Karunaratne Yasiru G. , Gunaratne Dakshika A. , Veness Michael J.
Published: June 2018

Background

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine tumor arising on the head and neck in 40%‐50% of patients. Between 20% and 40% will harbor subclinical nodal metastasis.

Methods

Using search terms ‘Merkel AND sentinel’, MEDLINE, PUMED, and EMBASE databases were systematically reviewed for publications regarding sentinel lymph node biopsy (SLNB) in classification I and II MCC of the head and neck.

Results

Twenty‐nine publications encompassing 136 patients were included. The SLNB finding was positive in 42 patients (30.9%). Primary MCC was located on the malar/zygomatic (34.4%), forehead/frontal (13.5%), and nasal (13.5%) regions. Recurrence in an SLNB negative nodal basin result occurred in 10 patients (false negative rate of 19.2%). Site of primary MCC was not associated with a false‐negative SLNB result; however, there was a non‐statistically significant trend for increased frequency among midline lesions.

Conclusions

Sentinel lymph node biopsy (SLNB) is recommended for eligible patients with classification I and II head and neck MCC.
Drug permeation and metabolism in Mycobacterium tuberculosis: Prioritising local exposure as essential criterion in new TB drug development
Authors: Tanner Lloyd , Denti Paolo , Wiesner Lubbe , Warner Digby F.
Published: June 2018

Anti‐tuberculosis (TB) drugs possess diverse abilities to penetrate the different host tissues and cell types in which infecting Mycobacterium tuberculosis bacilli are located during active disease. This is important since there is increasing evidence that the respective “lesion‐penetrating” properties of the front‐line TB drugs appear to correlate well with their specific activity in standard combination therapy. In turn, these observations suggest that rational efforts to discover novel treatment‐shortening drugs and drug combinations should incorporate knowledge about the comparative abilities of both existing and experimental anti‐TB agents to access bacilli in defined physiological states at different sites of infection, as well as avoid elimination by efflux or inactivation by host or bacterial metabolism. However, while there is a fundamental requirement to understand the mode of action and pharmacological properties of any current or experimental anti‐TB agent within the context of the obligate human host, this is complex and, until recently, has been severely limited by the available methodologies and models. Here, we discuss advances in analytical models and technologies which have enabled investigations of drug metabolism and pharmacokinetics (DMPK) for new TB drug development. In particular, we consider the potential to shift the focus of traditional pharmacokinetic–pharmacodynamic analyses away from plasma to a more specific “site of action” drug exposure as an essential criterion for drug development and the design of dosing strategies. Moreover, in summarising approaches to determine DMPK data for the “unit of infection” comprising host macrophage and intracellular bacillus, we evaluate the potential benefits of including these analyses at an early stage in the preclinical drug development algorithm. © 2018 IUBMB Life, 70(9):926–937, 2018
Targeting the messengers: Serine/threonine protein kinases as potential targets for antimycobacterial drug development
Authors: Khan Mehak Zahoor , Kaur Prabhjot , Nandicoori Vinay Kumar
Published: June 2018

The emergence of increasingly drug‐resistant Mycobacterium tuberculosis strains has become a crucial public health concern. In order to effectively treat tuberculosis, it is imperative to find newer drug targets, which are important for the in vivo bacterial survival and persistence. Phosphorylation based signaling cascades modulated by eukaryotic‐like serine/threonine protein kinases and phosphatase in M. tuberculosis, transduce extracellular stimuli to a cellular response ensuing pathogen's growth, persistence and pathogenesis. Of the 11 STPKs that M. tuberculosis genome encodes, three kinases, namely PknA, PknB and PknG and the sole serine/threonine phosphatase PstP are crucial for the intracellular survival of the bacteria. PknA and PknB regulates cell growth, cell wall synthesis and morphological changes during bacterial cell division; while PknG modulates metabolic changes in response to stress and aids in bacterial survival during latency like conditions. PstP functions to dephosphorylate STPKs and their substrates and hence is important at nearly all stages of infection. Here, we review the current knowledge on PstP, PknA, PknB and PknG based on the genetic, biochemical, and functional studies in M. tuberculosis physiopathology. We further explore the potential of these molecules as targets for therapeutic intervention and discuss the advancement made in the development of inhibitors against these targets. © 2018 IUBMB Life, 70(9):889–904, 2018
CIN‐TCP transcription factors: Transiting cell proliferation in plants
Authors: Sarvepalli Kavitha , Nath Utpal
Published: June 2018

Leaves are the most conspicuous planar organs in plants, designed for efficient capture of sunlight and its conversion to energy that is channeled into sustaining the entire biosphere. How a few founder cells derived from the shoot apical meristem give rise to diverse leaf forms has interested naturalists and developmental biologists alike. At the heart of leaf morphogenesis lie two simple cellular processes, division and expansion, that are spatially and temporally segregated in a developing leaf. In leaves of dicot model species, cell division occurs predominantly at the base, concomitant with the expansion and differentiation of cells at the tip of the lamina that drives increase in leaf surface area. The timing of the transition from one cell fate (division) to the other (expansion) within a growing leaf lamina is a critical determinant of final leaf shape, size, complexity and flatness. The TCP proteins, unique to plant kingdom, are sequence‐specific DNA‐binding transcription factors that control several developmental and physiological traits. A sub‐group of class II TCPs, called CINCINNATA‐like TCPs (CIN‐TCPs henceforth), are key regulators of the timing of the transition from division to expansion in dicot leaves. The current review highlights recent advances in our understanding of how the pattern of CIN‐TCP activity is translated to the dynamic spatio‐temporal control of cell‐fate transition through the transactivation of cell‐cycle regulators, growth‐repressing microRNAs, and interactions with the chromatin remodeling machinery to modulate phytohormone responses. Unravelling how environmental inputs influence CIN‐TCP‐mediated growth control is a challenge for future studies. © 2018 IUBMB Life, 70(8):718–731, 2018
Have we realized the full potential of β‐lactams for treating drug‐resistant TB?
Authors: Story‐Roller Elizabeth , Lamichhane Gyanu
Published: June 2018

β‐lactams are the most widely used antibiotics and are effective against a spectrum of pathogenic bacteria. Here, we focus on the state‐of‐the‐art understanding of the molecular underpinnings that determine the overall efficacy of β‐lactams against TB and include historical perspectives of this antibiotic class against this ancient disease. We summarize literature that describes why earlier generations of β‐lactams are ineffective and the potential promise of newer β‐lactams that exhibit improved efficacy against TB. Emerging evidence warrants renewed consideration of newer β‐lactams in regimens for treatment of drug‐resistant TB. © 2018 IUBMB Life, 70(9):881–888, 2018
Genetic association between SHANK2 polymorphisms and susceptibility to autism spectrum disorder
Authors: Bai Ye , Qiu Shuang , Li Yan , Li Yong , Zhong Weijing , Shi Meijuan , Zhu Xiaojuan , Jiang Huiyi , Yu Yaqin , Cheng Yi , Liu Yawen
Published: June 2018

Autism spectrum disorder (ASD), as one of early‐onset neurodevelopmental disorders, is characterized by the following symptoms, including repetitive and stereotyped behaviors, impairments in social interaction, and dysfunctions in communication. ASD afflicts ∼1.5% of children aged 8 years in America and ∼4.5‰ of children aged 0–6 years in China. Existing studies suggest that SH3 and multiple ankyrin repeat domains protein 2 (SHANK2) is implicated in ASD. However, associations between SNPs in SHANK2 introns and ASD risk have been less investigated. In this study, on the basis of case‐control study (226 cases and 239 controls), we selected nine SNPs (rs76717360, rs11236697, rs74336682, rs77950809, rs17428526, rs35459123, rs75357229, rs61887413, and rs77716438) in SHANK2 introns to investigate genetic associations between SHANK2 polymorphisms and susceptibility to ASD using improved multiple ligase detection reaction (iMLDR). We identified that the polymorphism of rs76717360 was associated with risk of ASD in Chinese population; the haplotype of rs11236697 C (T) or rs74336682 G (A) increased ASD risk; and haplotypes with ≥ five SNPs containing rs11236697 and rs74336682 were associated with risk of ASD. Our results indicate SHANK2 is a susceptibility gene for ASD in Chinese children. © 2018 IUBMB Life, 70(8):763–776, 2018
Genome wide analysis of meiotic recombination in yeast: For a few SNPs more
Authors: Chakraborty Parijat , Pankajam Ajith V. , Dutta Abhishek , Nishant Koodali T.
Published: June 2018

Diploid organisms undergo meiosis to produce haploid germ cells. Crossover events during meiosis promote genetic diversity and facilitate accurate chromosome segregation. The baker's yeast Saccharomyces cerevisiae is extensively used as a model for analysis of meiotic recombination. Conventional methods for measuring recombination events in S. cerevisiae have been limited by the number and density of genetic markers. Next generation sequencing (NGS)‐based analysis of hybrid yeast genomes bearing thousands of heterozygous single nucleotide polymorphism (SNP) markers has revolutionized analysis of meiotic recombination. By facilitating analysis of marker segregation in the whole genome with unprecedented resolution, this method has resulted in the generation of high‐resolution recombination maps in wild‐type and meiotic mutants. These studies have provided novel insights into the mechanism of meiotic recombination. In this review, we discuss the methodology, challenges, insights and future prospects of using NGS‐based methods for whole genome analysis of meiotic recombination. The objective is to facilitate the use of these high through‐put sequencing methods for the analysis of meiotic recombination given their power to provide significant new insights into the process. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 70(8):743–752, 2018
Centromere and its associated proteins—what we know about them in Plasmodium falciparum
Authors: Verma Garima , Surolia Namita
Published: June 2018

The complex life cycle of intracellular parasitic protozoans entails multiple rounds of DNA replication and mitosis followed by cytokinesis to release daughter parasites. To gain insights into mitotic events it is imperative to identify the biomarkers that constitute the chromosome segregation machinery in the parasite. Chromosomal loci called centromeres and their associated proteins play an essential role in accurate chromosome segregation. Although new information on the centromere‐kinetochore proteins has been added to the existing pool of knowledge, a paucity of biomarkers for nuclear division prevents a global view of chromosome segregation mechanism in the malaria parasite. In Plasmodium falciparum, except CENH3 and CENP‐C homologues, other centromere associated proteins responsible for centromere functions and kinetochore assembly are not known. The focus of this review is to summarize the current understanding on the centromere organization and its associated proteins in eukaryotes with the emerging information in P. falciparum. © 2018 IUBMB Life, 70(8):732–742, 2018
Efficacy and safety of a clinically relevant foamy vector design in human hematopoietic repopulating cells
Authors: Everson Elizabeth M. , Hocum Jonah D. , Trobridge Grant D.
Published: June 2018

Background

Previous studies have shown that foamy viral (FV) vectors are a promising alternative to gammaretroviral and lentiviral vectors and also that insulators can improve FV vector safety. However, in a previous analysis of insulator effects on FV vector safety, strong viral promoters were used to elicit genotoxic events. In the present study, we developed and analyzed the efficacy and safety of a high‐titer, clinically relevant FV vector driven by the housekeeping promoter elongation factor‐1α and insulated with an enhancer blocking A1 insulator (FV‐EGW‐A1).

Methods

Human CD34+ cord blood cells were exposed to an enhanced green fluorescent protein expressing vector, FV‐EGW‐A1, at a multiplicity of infection of 10 and then maintained in vitro or transplanted into immunodeficient mice. Flow cytometry was used to measure engraftment and marking in vivo. FV vector integration sites were analyzed to assess safety.

Results

FV‐EGW‐A1 resulted in high‐marking, multilineage engraftment of human repopulating cells with no evidence of silencing. Engraftment was highly polyclonal with no clonal dominance and a promising safety profile based on integration site analysis.

Conclusions

An FV vector with an elongation factor‐1α promoter and an A1 insulator is a promising vector design for use in the clinic.
Elucidating the mass spectrum of the retronecine alkaloid using DFT calculations
Authors: Modesto‐Costa Lucas , Martinez Sabrina T. , Pinto Angelo C. , Vessecchi Ricardo , Borges Itamar
Published: June 2018

Pyrrolizidine alkaloids are natural molecules playing important roles in different biochemical processes in nature and in humans. In this work, the electron ionization mass spectrum of retronecine, an alkaloid molecule found in plants, was investigated computationally. Its mass spectrum can be characterized by three main fragment ions having the following m/z ratios: 111, 94, and 80. In order to rationalize the mass spectrum, minima and transition state geometries were computed using density functional theory. It was showed that the dissociation process includes an aromatization of the originally five‐membered ring of retronecine converted into a six‐membered ring compound. A fragmentation pathway mechanism involving dissociation activation barriers that are easily overcome by the initial ionization energy was found. From the computed quantum chemical geometric, atomic charges, and energetic parameters, the abundance of each ion in the mass spectrum of retronecine was discussed.
Accelerated reactions in field desorption mass spectrometry
Authors: Chen Xingshuo , Cooks R. Graham
Published: June 2018

Field desorption mass spectrometry under ambient conditions is used to study solution‐phase organic reactions in micro‐volumes. Reagent solution is transferred onto the microdendrites of the field emitter, and reaction products are examined online by mass spectrometry. Three reactions, hydrazone formation by phenyl hydrazine and indoline‐2,3‐dione, the Katritzky reaction between a pyrylium salt and anisidine, and the Hantzsch synthesis of 1,4‐dihydropyridine, were investigated, and reaction acceleration was observed to different extents. The increase in rate relative to the corresponding bulk reactions is attributed to solvent evaporation (simple concentration effect) and to the increase of surface‐to‐volume ratio (enhanced interfacial reactions). A distinguishing feature of this method of reaction acceleration, relative to that based on nano electrospray ionization, is the observation of radical cations and the formation of radical cation products. The study also breaks new ground in using field emitters at atmospheric pressure.
The hypolipidemic effects of peptides prepared from Cicer arietinum in ovariectomized rats and HepG2 cells
Authors: Shi Wen , Hou Tao , Liu Weiwei , Guo Danjun , He Hui
Published: June 2018

BACKGROUND

The lack of estrogen in postmenopausal women is a key risk factor for disorders of lipid metabolism and for obesity. Except in cases where estrogen replacement therapy (ERT) is being used, chickpea peptides (ChPs) may be a potential candidate for treating hyperlipidemia.

RESULTS

In ovariectomized rats model, ChPs were found to decrease body weight, adipose tissue size, total cholesterol (TC), total triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), and the atherogenic index (AI) in serum and liver TC and TG. Serum high‐density lipoprotein cholesterol (HDL‐C), bile acids in liver and feces, fecal TC and TG were observed to increase significantly (P < 0.05). ChPs play a role in inhibiting the activities of fatty acid synthetase (FAS) and HMG‐CoA reductase (HMGR). The expression of peroxisome proliferator‐activated receptors (PPAR)γ and sterol regulatory element‐binding protein (SREBP)‐1c were downregulated and the expression of liver X receptor (LXR) α, estrogen receptor(ER)α and ERβ were upregulated by ChPs. In HepG2 cell experiments, the cellular TC levels decreased and the uptake of NBD‐cholesterol increased significantly after treatment with Mw < 1 kDa and Mw < 5 kDa ChPs fractions. Val‐Phe‐Val‐Arg‐Asn (VFVRN) could inhibit TC biosynthesis by decreasing the expression of HMGR.

CONCLUSION

We demonstrated that ChPs could effectively regulate lipid metabolism disorders and restrain obesity caused by estrogen deficiency. Val‐Phe‐Val‐Arg‐Asn identified from ChPs could reduce the expression of HMGR to inhibit cholesterol biosynthesis. © 2018 Society of Chemical Industry
Tgfbr2 is required in Acan‐expressing cells for maintenance of the intervertebral and sternocostal joints
Authors: Alkhatib Bashar , Liu Cunren , Serra Rosa
Published: June 2018

Background

Members of the transforming growth factor beta (TGF‐β) family are secreted proteins that regulate skeletal development. TGF‐β signaling is critical in embryonic development of the annulus fibrosus (AF) of the intervertebral disc (IVD). To address the question of the role of TGF‐β signaling in postnatal development and maintenance of the skeleton, we generated mice in which Tgfbr2 was deleted at 2‐weeks of age in Aggrecan (Acan)‐expressing cells using inducible Cre/LoxP recombination.

Methods

Localization of Cre recombination was visualized by crossing Acantm1(cre/ERT2)Crm mice to fluorescent mTmG reporter mice. Acantm1(cre/ERT2)Crm mice were mated to Tgfbr2LoxP/LoxP mice and Cre recombinase was activated by tamoxifen injection at 2‐weeks postnatally. Following tamoxifen injection, mice were aged to 3, 6, and 12‐months and control mice were compared to the experimental (cKO) group. Mice were initially analyzed using X‐ray and skeletal preparations. Sternocostal joints and IVD tissues were further analyzed histologically by hematoxylin and eosin (H&E), Safranin O, and Picrosirius Red staining as well as Col10 immunostaining.

Results

Cre recombination was observed in the IVD and sternocostal joints. X‐ray analysis revealed osteophyte formation within the disc space of 12‐month‐old cKO mice. Skeletal preparations confirmed calcification within the IVD and the sternocostal joints in cKO mice. H&E staining of cKO IVD revealed disorganized growth plates, delay in the formation of the bony endplate, and Col10 staining in the AF indicative of ectopic endochondral bone formation. Furthermore, proteoglycan loss was observed and collagen bundles within the inner AF were thinner and less organized. Alterations in the IVD were apparent beginning at 3 months and were progressively more visible at 6 and 12 months. Similarly, histological analysis of cKO sternocostal joints revealed joint calcification, proteoglycan loss, and disorganization of the collagen architecture at 12 months of age.

Conclusions

TGF‐β signaling is important for postnatal development and maintenance of fibrocartilaginous IVD and sternocostal joints.
Urinary l‐kynurenine quantification and selective extraction through a molecularly imprinted solid‐phase extraction device
Authors: Mergola Lucia , Orabona Ciriana , Albini Elisa , Vasapollo Giuseppe , Scorrano Sonia , Del Sole Roberta
Published: June 2018

l‐Kynurenine is an endogenous metabolite generated by the catabolic pathway of l‐tryptophan and it could be a potential biomarker to test the efficacy of several checkpoint inhibitors that have already reached the clinical trials in the antitumor therapy. Thus, a molecularly imprinted polymer specific for the recognition of this metabolite was synthesized and used as innovative system in solid‐phase extraction technique for the specific extraction and quantification of l‐kynurenine in human urine. The off‐line system was firstly tested on l‐kynurenine standard solutions, allowing recoveries up to 97.7% (relative standard deviation = 2.2%) and then applied to fortified and deproteinated human urine samples, where a recovery of 84.1% (relative standard deviation = 3.1%) was obtained. The method was validated and it revealed a good linearity in the range of 0.157–20 μg/mL (r2 = 0.9992). The optimized procedure demonstrated a good feasibility on biological samples, allowing a ready quantification of l‐kynurenine in the human urine, where the metabolite was found at a very low concentration (0.80 μg/mL). The extraction system developed could attract attention of pharmaceutical industries for l‐kynurenine production as potential drug in the treatment of autoimmune disorders through its extraction and purification from biological matrixes.
Comparing yield and growth characteristics of four pastoral plant species under two salinity soil levels
Authors: Tlili Abderrazak , Tarhouni Mohamed , Cerdà Artemi , Louhaichi Mounir , Neffati Mohamed
Published: June 2018

The vegetation cover and the biomass production of the rangeland ecosystems are decreasing at an alarming rate. The valorization of saline water, by irrigating planted pastoral halophytes on salt‐affected soils, is considered among the valuable tools to increase their production. In this study, the ability of four plant species (Atriplex halimus L. [Amaranthaceae], Atriplex mollis Desf. [Amaranthaceae], Lotus creticus L. [Fabaceae], and Cenchrus ciliaris L. [Poaceae]) to grow is tested in two field plots—low (low salinity plot [LSP]) and high (high salinity plot [HSP]) soil salinity. Canopy cover, dry biomass, and some chemical analyses (ash, nitrogen, and polyphenol contents) are undertaken. Main results show that A. halimus is the most able to grow in the two plots because it shows the greatest covers during the experiment. The covers of others species are low both in LSP and HSP. A. mollis retains the highest dry matter in both LSP (157 and 236 g) and HSP (134 and 153 g) when cutting 1/2 and 2/3 of the aboveground biomass, respectively. A. halimus and A. mollis have the biggest ash content in both LSP (respectively 65 and 67.5 mg g−1 fresh matter) and HSP (112.5 and 100 mg g−1 fresh matter). L. creticus and A. halimus show the highest total nitrogen content in LSP (respectively 26.9 and 26.3 g kg−1 dry matter). All the species reduced their nitrogen in HSP despite the C. ciliaris content that remains constant. In conclusion, the ability of the retained species to grow under high soil salinity is noted. Hence, the saline soils can be rehabilitated by planting well‐targeted pastoral halophytes.