bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on the Comprehensive Approach to Fragility Fractures
Authors: Cohn Matthew R. , Gianakos Arianna L. , Grueter Kirsten , Rosen Natalie , Cong Guang-Ting , Lane Joseph M.
Published: July 2018

The prevention and treatment of fragility fractures continuously evolve. Adequate fracture care should involve treating the fracture itself and the underlying bone disease. Although effective treatments of osteoporosis are available, a large proportion of patients with fragility fractures are not prescribed antiosteoporotic medications after their injury. Recent advances in diagnostic tools, medications, and implementation of Fracture Liaison Services allow for more effective and comprehensive treatment or fragility fractures. In the Fracture Liaison Service model, a physician and physician extenders coordinate care. This includes a thorough medical and surgical history, metabolic bone disease laboratory testing, dual-energy x-ray absorptiometry screening, treatment, and long-term follow-up. Treatment options include nonpharmacologic treatment with calcium and vitamin D and antiresorptive and anabolic agents. Antiresorptive agents such as bisphosphonates and denosumab are first-line treatments for osteoporosis and anabolic agents such as teriparatide are effective in reducing bone density loss and have implications in fracture healing. In addition, new anabolic agents including antisclerostin antibodies and parathyroid hormone-related protein show promise as potential treatments to increase bone density.
Gram Stain is Not Clinically Relevant in Treatment of Pediatric Septic Arthritis
Authors: Bram Joshua T. , Baldwin Keith D. , Blumberg Todd J.
Published: July 2018

Background:

The diagnosis of pediatric septic arthritis (SA) can be challenging due to wide variability in the presentation of musculoskeletal infection. Synovial fluid Gram stain is routinely obtained and often used as an initial indicator of the presence or absence of pediatric SA. The purpose of this study was to examine the clinical utility of the Gram stain results from a joint aspiration in the diagnosis and management of pediatric SA.

Methods:

All patients with suspected SA who underwent arthrocentesis and subsequent surgical irrigation and debridement at an urban tertiary care children’s hospital between January 2007 and October 2016 were identified. Results of the synovial fluid Gram stain, as well as synovial cell count/differential and serum markers, were evaluated.

Results:

A total of 302 patients that underwent incision and drainage for suspected SA were identified. In total, 102 patients (34%) had positive synovial fluid cultures and 47 patients (16%) had a microorganism detected on Gram stain. Gram stain sensitivity and specificity for the detection of SA were 0.40 and 0.97, respectively. This yielded a number needed to misdiagnose of 4.5 (ie, every fifth patient was misdiagnosed by Gram stain). For gram-negative organisms, the sensitivity dropped further to 0.13, with only 2/16 gram-negative organisms identified on Gram stain. Stepwise regression showed that age, serum white blood cell, and absolute neutrophil count were significant independent predictors for having a true positive Gram stain result. Elevated synovial white blood cell count was a significant predictor of having an accurate (culture matching the Gram stain) result.

Conclusions:

The Gram stain result is a poor screening tool for the detection of SA and is particularly ineffective for the detection of gram-negative organisms. The clinical relevance of the Gram stain and cost-effectiveness of this test performed on every joint aspiration sent for culture requires additional evaluation. Patients with gram-negative SA may be at high risk for inadequate coverage with empiric antibiotics due to poor detection of gram-negative organisms on initial Gram stain.

Level of Evidence:

Level III—case-control study.
New insights in the pathogenesis of T-cell lymphomas
Authors: Lemonnier François , Gaulard Philippe , de Leval Laurence
Published: July 2018

Purpose of review

Peripheral T-cell lymphomas (PTCLs) represent diverse and aggressive malignancies, with few recent therapeutic improvements. Recent high-throughput genomic studies have revealed the complex mutational landscape of these rare diseases. These novel findings provide the grounds to a more comprehensive classification of these diseases, reflected in the 2017 WHO classification.

Recent findings

Our review is focused on selected PTCL entities. Angioimmunoblastic T-cell lymphoma and other lymphomas derived from T follicular helper cells feature a rather homogeneous mutational landscape. These neoplasms recapitulate a multistep oncogenic process associating epigenetic deregulation, and second hit mutations affecting the T-cell receptor signaling pathway. This model inferred from comprehensive analyses of patients samples, was confirmed in mouse models. Among ALK-negative anaplastic large-cell lymphomas, translocation-associated subsets are found in both systemic and cutaneous types, and the newly described breast implant-associated type is usually indolent. Extranodal lymphomas of the innate immune system also harbor a combination of mutations affecting different classes of epigenetic modifiers, and mutation-induced activation of the Janus Kinase/signal transduction and activator of transcription pathway.

Understanding of PTCL pathogenesis has substantially improved, and oncogenic events have been identified. The current challenge is to mount efficient therapeutic strategies targeting these aberrations to improve patients’ outcome.
The Optimal Diameter for Circumpapillary Retinal Nerve Fiber Layer Thickness Measurement by SD-OCT in Glaucoma
Authors: Heindl Ludwig M. , Adler Werner , El-Malahi Ouahiba , Schaub Friederike , Hermann Manuel M. , Dietlein Thomas S. , Cursiefen Claus , Enders Philip
Published: July 2018

Purpose:

To evaluate the diagnostic power for glaucoma detection using circumpapillary retinal nerve fiber layer (cRNFL) thickness in 3 diameter sizes from the center of the optic nerve head (ONH) by spectral domain optical coherence tomography.

Patients and Methods:

In this cross-sectional study, case-control, 437 eyes diagnosed with glaucoma and 183 eyes of healthy controls underwent spectral domain optical coherence tomography of the ONH, visual field testing, and a clinical examination. cRNFL was measured by circular scans in 3.5 (C1), 4.1 (C2), and 4.7 mm (C3) distance from the center of the ONH. Receiver-operator characteristic analysis was used to assess diagnostic power to detect glaucoma; furthermore, patient-specific maximum localized damage was analyzed.

Results:

In C1, mean global cRNFL was 70.03±18.2 μm in glaucomatous eyes and 93.46±9.9 μm in controls. Respectively, cRNFL in C2 was 61.39±14.9 and 80.43±8.4 μm as well as 55.25±12.8 and 70.70±6.7 μm in C3. Using receiver-operator characteristic analysis, the area under the curve (AUC) for cRNFL was 0.855 in C1, 0.850 in C2, and 0.843 in C3. Mean AUCs in ONH sectors ranged from 0.699 to 0.846 and did not exceed AUC of the best scoring global parameter.

Conclusions:

Comparing 3.5, 4.1, and 4.7 mm diameters for cRNFL measurement, the inner circle at 3.5 mm distance showed the highest AUC to differentiate glaucoma from healthy controls. However, levels of diagnostic power from wider circular scans were not significantly different and were comparable. Moreover, sectorial cRNFL measurements were nonsuperior. The use of the ONH sector with the highest localized damage seems not to increase diagnostic power.
Minimally Invasive Mitral Repair
Authors: Barac Yaron D. , Glower Donald D.
Published: July 2018

The right 2nd interspace minithoracotomy has advantages over femoral arterial cannulation providing an alternative that should be in the arsenal of the minimally invasive surgeon; we describe here the method, the advantages, and the pitfalls.
Acuity-based Scheduling in Primary Care
Authors: Candon Molly , Rhodes Karin , Polsky Daniel
Published: July 2018

Objectives:

Triage algorithms are ubiquitous in emergency care settings, but the extent of their use in primary care is unknown. This study asks whether primary care practices prioritize patients with more acute service needs.

Methods:

We used an audit study in which simulated patients were randomized to 2 clinical scenarios—a new patient seeking a routine check-up or a new patient seeking treatment for newly diagnosed hypertension—and attempted to schedule appointments with thousands of randomly selected primary care physicians across 10 states. We estimated the difference in appointment availability by clinical scenario. For scheduled appointments, we also estimated the difference in wait times by clinical scenario.

Results:

While there was no difference in appointment availability, the mean wait time for simulated patients seeking a routine check-up was nearly 5 days longer than the mean wait time for simulated patients with hypertension.

Conclusions:

As demand for primary care increases while the supply remains stable, it will be important for practices to identify and prioritize patients with more acute service needs. Our results show that primary care physicians are already adopting such practices.
The plasma contact system as a modulator of innate immunity
Authors: Wu Yi
Published: July 2018

Purpose of review

The contact system is a plasma protease cascade, which activates the proinflammatory kallikrein–kinin system and the procoagulant intrinsic coagulation pathway. Recent advances demonstrating the novel functions of this system as a key player of innate immune system will be introduced in the present review.

Recent findings

The role of the contact system is to initiate and participate in pathophysiological responses to injury, mainly the processes of coagulation and inflammation. The past few years have seen substantial progress, showing a new role of this system in regulation of innate immunity. The relationship between high-molecular-weight kininogen and lipopolysaccharide (LPS) has been investigated and a new function of high-molecular-weight kininogen has been identified as the critical LPS carrier supporting endotoxemia. In contrast, the role of high-molecular-weight kininogen in Klebsiella pneumoniae sepsis is limited. Coagulation factor XII (FXII) plays a detrimental role in murine wound healing and host defense against K. pneumoniae sepsis. In the pathogenesis of arthritis and colitis, the activation of plasma kallikrein and downstream cleavage of high-molecular-weight kininogen and release of bradykinin constitutes a critical pathway in the innate immune mechanism, whereas FXII is not important.

Current findings indicate that the plasma contact system functions as an important constituent of innate immune system, contributing to the pathogenesis of the immunological and infectious diseases.
Lack of Uptake of Prophylactic Human Papilloma Virus Vaccine Among Women With Systemic Lupus Erythematosus Seen at a Regional Medical Center
Authors: Dhar Josephine Patricia , Essenmacher Lynnette , Dhar Renee , Ragina Neli , Sokol Robert J.
Published: July 2018

Background/Objective

Women with systemic lupus erythematosus (SLE) are at increased risk for cervical neoplasia likely due to infection with high-risk human papillomavirus (HR-HPV) and should be considered for HPV vaccination. We sought to determine the frequency of HR-HPV infection and uptake of HPV vaccination in our regional female lupus population.

Methods

For this medical records review study, data were analyzed from our electronic health records EPIC for women with International Classification of Diseases-10 or International Classification of Diseases -9 billing codes for SLE seen June 6, 2007, to May 1, 2017. This study was approved by the Central Michigan University/Covenant Medical Center institutional review board. Statistical analyses consisted of Student t test, χ2, and Z test for proportions using SPSS v. 24 software.

Results

A total of 1349 women with SLE were identified, mean age of 53 years, 70.8% white, 20.8% African American, with 49% exposed to cigarette smoke. High-risk HPV testing performed in 195 (14.5%; mean age, 50 years) showed 16.9% (33/195) were positive, with those testing positive for HR-HPV being slightly younger (p < 0.05).

Comparing our proportion testing positive for HR-HPV (0.169) versus National Health and Nutrition Examination Survey (0.088), we calculated a Z = 3.99 (p < 0.001) indicating HPV infection is significantly higher (2×) in our female SLE cohort. Only 16.0% (38/238) of the 238 women eligible to receive an HPV vaccine were tested for HR-HPV with 9 being positive and only 4.6% (11/238) vaccinated.

Conclusions

Human papillomavirus infection is a serious health issue in women with SLE, but HPV testing and vaccination rates remain low. Efforts should be directed to promote awareness of the importance of HPV vaccination in this high-risk population.
The Montreal Cognitive Assessment Test
Authors: Paez-Venegas Nicolas , Jordan-Estrada Bethel , Chavarria-Avila Efrain , Perez-Vazquez Felipe , Gómez-Bañuelos Eduardo , Medina-Dávalos Rafael , Ontiveros-González José-Ángel , Diaz-Rubio Gustavo-Ignacio , Navarro-Hernandez Rosa E. , Vázquez-Del Mercado Mónica
Published: July 2018

Background/Objective

Systemic lupus erythematosus (SLE) is an inflammatory, chronic, and multisystemic disease, which may be associated with a wide range of neuropsychiatric manifestations, including cognitive impairment. Cognitive evaluations based on screening tests might identify early SLE-related cognitive alterations. The aim of this study was to evaluate and to compare the efficacy of three screening tests (Montreal Cognitive Assessment [MoCA], Mini Mental State Examination [MMSE], Cognitive Symptom Inventory [CSI]) against the gold standard (neuropsychological battery), in order to identify the most efficient screening test for cognitive impairment in patients with SLE.

Methods

This observational cross-sectional study recruited 44 patients, from August to December 2017, who were diagnosed with SLE according to the Systemic Lupus International Collaborating Clinics (SLICC) Criteria 2012, and had no medical or psychiatric comorbidities. The patients were evaluated using the MoCA, MMSE, CSI, and the gold standard. Spearman’s correlation and area under the curve analysis were performed; p < 0.05 was considered significant.

Results

The MoCA test showed the highest correspondence with the gold standard (AUC = 99.4%, p < 0.001), sensitivity (84%), and specificity (100%). This was followed by the MMSE (AUC = 92.6%, p < 0.001; sensitivity, 54.8%; specificity, 100%) and the CSI (AUC = 30.6%, p < 0.05; sensitivity, 54.8%; specificity, 30.76%).

Conclusion

The MoCA is a brief, easily applied screening test that is highly effective for detecting cognitive impairment in SLE patients. It could be useful in clinical follow-up as a tool for early detection of cognitive alterations.
Half-dose Coronary Artery Calcium Scoring
Authors: Caruso Damiano , De Santis Domenico , Biondi Tommaso , Panvini Nicola , Zerunian Marta , Rivosecchi Flaminia , Montesano Marta , Bellini Davide , Rengo Marco , Laghi Andrea
Published: July 2018

Purpose:

The purpose of this study was to assess the impact of adaptive statistical iterative reconstruction (ASiR) on half-dose coronary artery calcium scoring (CACS) acquisition protocol.

Materials and Methods:

Between September 2016 and October 2017, 89 patients (54 male patients, mean age 64.6±10.7 y) with a clinically indicated coronary computed tomography angiography were prospectively enrolled. On a 64-row computed tomography scanner, patients underwent a standard CACS protocol (120 kVp, 170 mAs) reconstructed by filtered-back projection, and a half-dose CACS protocol (120 kVp, 85 mAs) reconstructed by ASiR at different percentages, from 10% to 100%, in 10% increments. CACS determinants (Agatston score, number of plaques, volume, and mass), signal-to-noise ratio, contrast-to-noise ratio, and radiation dose of both protocols were calculated. Patient risk categories based on CACS were determined for each protocol, and analysis of risk reclassification of half-dose protocol was performed. Depending on their body mass index (BMI), patients were divided into nonobese (BMI<30 kg/m2) and obese (BMI≥30 kg/m2) groups to investigate the influence of BMI on CACS determinants and risk reclassification.

Results:

Half-dose protocol reconstructed with ASiR 70% showed no significant differences in any CACS determinant compared with the standard protocol for both nonobese and obese patients (all P≥0.070 and ≥0.066, respectively) and reclassified 1 (1.7%) and 6 (20.0%) patients, respectively, with excellent (κ=0.91) and good (κ=0.74) agreement with standard protocol, respectively. ASiR 70% also resulted in a higher signal-to-noise ratio (1.88±0.78) and contrast-to-noise ratio (7.10±2.73) compared with standard protocol (all P≤0.001). Half-dose protocol provided 52% less radiation dose than standard acquisition (0.31±0.06 vs. 0.64±0.10 mSv; P<0.001).

Conclusions:

ASIR 70% coupled with reduction of tube current by 50% allowed for significant dose reduction and no detrimental effects on image quality, with minimal patient reclassification in nonobese patients. In obese patients, excessive noise may lead to a clinically significant reclassification rate.
Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis
Authors: Kawamoto Eiji , Masui-Ito Asami , Eguchi Akiko , Soe Zay Yar , Prajuabjinda Onmanee , Darkwah Samuel , Park Eun Jeong , Imai Hiroshi , Shimaoka Motomu
Published: July 2018

Extracellular vesicles (EVs) in the plasma mediate important intercellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programmed cell death ligand 1 and 2 (PD-L1 and 2) that suppress lymphocyte activation. However, the roles of these molecules on EVs in systemic inflammatory response syndrome (SIRS) and sepsis remain little understood. This study aimed to investigate how the EV expression of integrins and PD-1 ligands might differ in SIRS and sepsis, compared with healthy controls, and to correlate their expression with the clinical parameters reflecting pathogenesis. Twenty-seven SIRS patients without sepsis, 27 sepsis patients, and 18 healthy volunteers were included. EVs were isolated from plasma samples. The expression of three major integrins (β1, β2, β3 integrins) and PD-L1 and 2 were measured. The EV expression of β2 integrin and PD-L2 was significantly increased in sepsis patients compared with healthy controls. EV expression of PD-L1 was not elevated in sepsis and SIRS; however, circulating soluble PD-L1 levels were significantly higher in sepsis. Furthermore, EV expression of β2 integrin in sepsis patients correlated with hypotension and reduced kidney function. In addition, soluble PD-L1 levels correlated with sepsis severity, impaired kidney function, and impaired central nervous system function. These results suggest the potential involvements of the EV β2 integrin, as well as EV PD-L2 and soluble PD-L1, in the septic pathogenesis that occurs with the systemic immune activation leading to multiple organ dysfunctions.
Outcomes of Adult Intestinal Transplant Recipients Requiring Dialysis and Renal Transplantation
Authors: Puttarajappa Chethan M. , Hariharan Sundaram , Humar Abhinav , Paliwal Yuvika , Gao Xiaotian , Cruz Ruy J. , Ganoza Armando J. , Landsittel Douglas , Bhattarai Manoj , Sogawa Hiroshi
Published: July 2018

Background

Data on dialysis and renal transplantation (RT) after intestinal transplantation (IT) are sparse. Whether changes in immunosuppression and surgical techniques have modified these outcomes is unknown.

Methods

Two hundred eighty-eight adult intestinal transplants performed between 1990 and 2014 at the University of Pittsburgh were analyzed for incidence, risk factors and outcomes after dialysis and RT. Cohort was divided into 3 eras based on immunosuppression and surgical technique (1990-1994, 1995-2001, and 2001-2014). Receiving RT, or dialysis for 90 days or longer was considered as end-stage renal disease (ESRD).

Results

During a median follow-up of 5.7 years, 71 (24.7%) patients required dialysis, 38 (13.2%) required long-term dialysis and 17 (6%) received RT after IT. One-, 3-, and 5-year ESRD risk was 2%, 7%, and 14%, respectively. No significant era-based differences were noted. Higher baseline creatinine (hazard ratio [HR], 3.40 per unit increase, P < 0.01) and use of liver containing grafts (HR, 2.01; P = 0.04) had an increased ESRD risk. Median patient survival after dialysis initiation was 6 months, with a 3-year survival of 21%. Any dialysis (HR, 12.74; 95% CI 8.46-19.20; P < 0.01) and ESRD (HR, 9.53; 95% CI, 5.87-15.49; P < 0.01) had higher mortality after adjusting for covariates. For renal after IT, 1- and 3-year kidney and patient survivals were 70% and 49%, respectively. All graft losses were from death with a functioning graft, primarily related to infectious complications (55%).

Conclusions

In intestinal transplant recipients, renal failure requiring dialysis or RT is high and is associated with increased mortality. Additionally, the outcomes for kidney after IT are suboptimal due to death with a functioning graft.
Low Dimensional Activity in Spiking Neuronal Networks
Authors: Wärnberg Emil , Kumar Arvind
Published: July 2018

Several recent studies have shown that neural activityin vivotends to be constrained to a low-dimensional manifold. Such activity does not arise in simulated neural networks with homogeneous connectivity and it has been suggested that it is indicative of some other connectivity pattern in neuronal networks. Surprisingly, the structure of the intrinsic manifold of the network activity puts constraints on learning. For instance, animals find it difficult to perform tasks that may require a change in the intrinsic manifold. Here, we demonstrate that theNeural Engineering Framework(NEF) can be adapted to design a biologically plausible spiking neuronal network that exhibit low dimensional activity. Consistent with experimental observations, the resulting synaptic weight distribution is heavy-tailed (log-normal). In our model, a change in the intrinsic manifold of the network activity requires rewiring of the whole network, which may be either not possible or a very slow process. This observation provides an explanation of why learning is easier when it does not require the neural activity to leave its intrinsic manifold.

Significance statement

A network in the brain consists of thousands of neurons. A priori, we expect that the network will have as many degrees of freedom as its number of neurons. Surprisingly, experimental evidence suggests that local brain activity is confined to a space spanned by 10 variables. Here, we describe an approach to construct spiking neuronal networks that exhibit low-dimensional activity and address the question: how the intrinsic dimensionality of the network activity restricts the learning as suggested by recent experiments? Specifically, we show that tasks that requires animals to change the network activity outside the intrinsic space would entail large changes in the neuronal connectivity, and therefore, animals are either slow or not able to acquire such tasks.
Atomic force microscopy reveals new biomarkers for monitoring subcellular changes in oxidative injury: neuroprotective effects of quercetin at the nanoscale
Authors: Jembrek Maja Jazvinšćak , Vlainić Josipa , Čadež Vida , Šegota Suzana
Published: July 2018

Oxidative stress is a process involved in the pathogenesis of many diseases, including atherosclerosis, hypertension, diabetes, Alzheimer’s disease etc. The biomarkers for assessing the degree of oxidative stress have been attracting much interest because of their potential clinical relevance in understanding cellular effects of free radicals and evaluation of the efficacy of drug treatment. Here, an interdisciplinary approach using atomic force microscopy (AFM) and cellular and biological molecular methods were used to obtain new potential biomarkers for monitoring oxidative stress condition. Biological methods confirmed the oxidative damage of investigated P19 neurons and revealed the underlying mechanism of quercetin protective action. AFM was employed to evaluate morphological (roughness) and nanomechanical (elasticity) properties that may be specific biomarkers for oxidative stress-induced cytoskeletal reorganization manifested by changes in the lateral dimension and height of neuronal somas. The morphological and nanomechanical analysis of neurons showed the strong mutual correlation between changes in cell membrane elasticity and neuroprotective effects of quercetin. Our findings indicate that AFM is a highly valuable tool for biomedical applications, detection and clarifying of drug-induced changes at the nanoscale and emphasize the potential of AFM approach in the development of novel therapeutic strategies directed against oxidative stress-induced neurodegeneration.
IL-2 Modulates Th2 cell Responses to Glucocorticoid: A Cause of Persistent Type 2 Inflammation?
Authors: Kanagalingam Tharsan , Vijeyakumaran Meerah , Palikhe Nami Shrestha , Solomon Lauren , Vliagoftis Harissios , Cameron Lisa
Published: July 2018

Background

Inhaled glucocorticosteroids (GCs) are the main treatment for asthma as they reduce type 2 cytokine (IL-4, IL-5 and IL-13) expression and induce apoptosis. Asthma severity is associated with GC insensitivity, increased type 2 inflammation and circulating Th2 cells. Since IL-2 is a T cell survival factor, we assessed whether IL-2 levels associate with the proportion of Th2 cells and/or correlate with clinical features of asthma severity.

Methods

Peripheral blood from asthma patients (n=18) was obtained and Th2 cell numbers determined by flow cytometry. Peripheral blood cells were activated with mitogen (24hrs) and supernatant levels of IL-2 and IL-13 measured by ELISA.In vitrodifferentiated Th2 cells were treated with dexamethasone and IL-2 and assessed for apoptosis by flow cytometry staining of Annexin V. Level of mRNA for anti-apoptotic (BCL-2) and pro-apoptotic (BIM) genes as well as IL-13 were determined by qRT-PCR.

Results

IL-2 produced by activated peripheral blood cells correlated negatively with lung function (FEV1) and positively with daily dose of inhaled GC. When patients were stratified based on IL-2 level, high IL-2 producers made more IL-13 and had more circulating Th2 cells.In vitro, increasing the level of IL-2 in the culture media was associated with resistance to DEX-induced apoptosis, more BCL-2 and less BIM mRNA. Th2 cells cultured with higher IL-2 also had more IL-13 mRNA and required higher concentrations of DEX for cytokine suppression.

Conclusions and Clinical Relevance

IL-2 modulates Th2 cell responses to GC, supporting both their survival and pro-inflammatory capacity, suggesting that a patient’s potential to produce IL-2 may be a determinant in asthma severity.
Impaired miRNA processing by DICER1 downregulation endows thyroid cancer with increased aggressiveness
Authors: Ramírez-Moya Julia , Wert-Lamas León , Riesco-Eizaguirre Garcilaso , Santisteban Pilar
Published: July 2018

The global downregulation of miRNAs (miRs) is emerging as a common hallmark of cancer. However, the mechanisms underlying this phenomenon are not well known. We identified that the oncogenic miR-146b-5p attenuates miRNA biosynthesis by targeting DICER1 and reducing its expression. DICER1 overexpression inhibited all the miR-146b-induced aggressive phenotypes in thyroid cells. Systemic injection of an antimiR-146b in mice with orthotopic thyroid tumors suppressed tumor growth and recovered DICER1 levels. Notably, DICER1 downregulation promoted proliferation, migration, invasion and epithelial-mesenchymal transition through miR downregulation. Our analysis of TCGA revealed a general decrease in DICER1 expression in thyroid cancer that was associated with a worse clinical outcome. Administration of the small molecule enoxacin to promote DICER1 complex activity reduced tumor aggressiveness bothin vitroandin vivo. Overall, our data establish DICER1 as a tumor suppressor and that the oncogenic miR-146b contributes to its downregulation. Moreover, this study highlights a potential therapeutic application of RNA-based therapies including miR-inhibitors and restoration of the biogenesis machinery, which may provide treatments in for thyroid and other cancers.
Increased GITRL impairs the function of MDSCs and exacerbates primary Sjögren’s syndrome
Authors: Tian Jie , Rui Ke , Hong Yue , Lin Xiang , Wang Xiaohui , Xiao Fan , Xu Huaxi , Lu Liwei , Wang Shengjun
Published: July 2018

It is largely unclear how MDSCs contribute to the development of primary Sjögren’s syndrome (pSS). In experimental SS (ESS) mice, MDSCs were significantly increased but exhibited gradually diminished suppressive capacity during the disease progression. The ligand for glucocorticoid-induced TNFR family-related protein (GITRL) was increased with the development of pSS, and the increased GITRL was found to down-regulate the function of MDSCs while blocking GITR signal in MDSCs significantly restored their function and ameliorated ESS progression in mice. In pSS patients, expanded MDSCs expressed lower level of arginase were observed in patients with higher SSDAI. Moreover, the increased GITRL in serum was also found to closely correlate with the aberrant function of MDSCs. Together, our studies have demonstrated a critical role of GITRL in modulating the suppressive capacity of MDSCs in pSS, which may facilitate the validation of GITRL as a therapeutic target for the treatment of pSS.
Psychoactive plant- and mushroom-associated alkaloids from two behavior modifying cicada pathogens
Authors: Boyce Greg R. , Gluck-Thaler Emile , Slot Jason C. , Stajich Jason E. , Davis William J. , James Tim Y. , Cooley John R. , Panaccione Daniel G. , Eilenberg Jørgen , Licht Henrik H. De Fine , Macias Angie M. , Berger Matthew C. , Wickert Kristen L. , Stauder Cameron M. , Spahr Ellie J. , Maust Matthew D. , Metheny Amy M. , Simon Chris , Kritsky Gene , Hodge Kathie T. , Humber Richard A. , Gullion Terry , Short Dylan P. G. , Kijimoto Teiya , Mozgai Dan , Arguedas Nidia , Kasson Matt T.
Published: July 2018

Entomopathogenic fungi routinely kill their hosts before releasing infectious spores, but select species keep insects alive while sporulating, which enhances dispersal. Transcriptomics and metabolomics studies of entomopathogens with post-mortem dissemination from their parasitized hosts have unraveled infection processes and host responses, yet mechanisms underlying active spore transmission by Entomophthoralean fungi in living insects remain elusive. Here we report the discovery, through metabolomics, of the plant-associated amphetamine, cathinone, in four Massospora cicadina-infected periodical cicada populations, and the mushroom-associated tryptamine, psilocybin, in annual cicadas infected with Massospora platypediae or Massospora levispora, which appear to represent a single fungal species. The absence of some fungal enzymes necessary for cathinone and psilocybin biosynthesis along with the inability to detect intermediate metabolites or gene orthologs are consistent with possibly novel biosynthesis pathways in Massospora. The neurogenic activities of these compounds suggest the extended phenotype of Massospora that modifies cicada behavior to maximize dissemination is chemically-induced.
A screen for gene regulators encoded by Kaposi’s sarcoma-associated herpesvirus uncovers a novel role for the ORF42 protein in regulating the production of cellular and viral proteins
Authors: Butnaru Matthew , Rivas Hembly , Gaglia Marta M.
Published: July 2018

The tight control of viral and host gene expression is critical to the replication of herpesviruses, including the gamma-herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV). While some of the KSHV proteins that contribute to viral and host gene regulation are known, it is clear that there are additional uncharacterized contributing viral factors. Identifying these proteins and their role in gene regulation is important to determine the mechanistic underpinnings of the complex replication cycle of KSHV. Through a reporter-based screen, we have identified several new potential KSHV-encoded gene regulators, including the previously uncharacterized protein ORF42, which we find stimulates global protein production upon overexpression. We have generated an ORF42-null virus, which revealed that ORF42 is required for wild-type levels of virus production. Moreover, global protein synthesis and the accumulation of viral proteins are reduced in infected cells in the absence of ORF42, suggesting that ORF42 regulates protein synthesis during infection. A comparison of the effects of ORF42 on the levels of RNA and protein suggests that ORF42 acts post-transcriptionally to control protein levels. In addition to gene regulation, ORF42 may have other functions in virion formation, as it is found in viral particles, which is consistent with the described roles of the ORF42 homologs in alpha- and beta-herpesviruses.

Importance

Kaposi’s sarcoma-associated herpesvirus (KSHV) causes Kaposi’s sarcoma, an AIDS-associated malignancy that remains one of the leading causes of cancer deaths in sub-Saharan Africa. Replication of the virus is important for tumor formation and inhibition of viral replication may be used for treatment. The correct levels and temporal expression of viral and host genes during KSHV replication are key to viral replication, but the mechanisms that control this regulation remain enigmatic. Here we identify several new KSHV proteins involved in viral and cellular gene regulation and characterize the previously unstudied KSHV ORF42 protein in regulation of viral and host protein levels and efficient formation of viral progeny.
Conjugation dynamics of self-transmissible and mobilisable plasmids intoE. coliO157:H7 onArabidopsis thalianarosettes
Authors: Remus-Emsermann Mitja N.P. , Pelludat Cosima , Gisler Pascal , Drissner David
Published: July 2018

Many antibiotic resistance genes present in human pathogenic bacteria are believed to originate from environmental bacteria and conjugation of antibiotic resistance conferring plasmids is considered to be one of the major reasons for the increasing prevalence of antibiotic resistances. A hotspot for plasmid-based horizontal gene transfer is the phyllosphere,i.e.the surfaces of aboveground plant parts. Bacteria in the phyllosphere might serve as intermediate hosts with transfer capability to human pathogenic bacteria. In this study, the exchange of mobilisable and self-transmissible plasmids via conjugation was evaluated. The conjugation from the laboratory strainE. coliS17-1, the model phyllosphere colonizerPantoea eucalypti299R, and the model pathogenE. coliO157:H7∆stxto the recipient strainE. coliO157:H7∷MRE1O3∆stxin the phyllosphere ofArabidopsis thalianawas determined. The results suggest that short-term occurrence of a competent donor is sufficient to fix plasmids in a recipient population ofE. coliO157:H7∷MRE1O3∆stx. The spread of self-transmissible plasmids was limited after initial steep increases of transconjugants that contributed up to 10% of the total recipient population. The here-presented data of plasmid transfer will be important for future modelling approaches to estimate environmental spread of antibiotic resistance in agricultural production environments.

Importance

This study investigated the transfer of antibiotic resistance conferring plasmids to enteropathogenicE. colion plant leaf surfaces. The results indicate that plasmid transfer may be high within the first 24 hours after inoculation. Transconjugant populations are maintained and stable for a considerable time frame on plant leaves, but invasion of the plasmid to the recipient population is limited.
A method for genome editing in the anaerobic magnetotactic bacteriumDesulfovibrio magneticusRS-1
Authors: Grant Carly R. , Rahn-Lee Lilah , LeGault Kristen N. , Komeili Arash
Published: July 2018

Magnetosomes are complex bacterial organelles that serve as model systems for studying cell biology, biomineralization, and global iron cycling. Magnetosome biogenesis is primarily studied in two closely related AlphaproteobacterialMagnetospirillumspp. that form cubooctahedral-shaped magnetite crystals within a lipid membrane. However, chemically and structurally distinct magnetic particles have also been found in physiologically and phylogenetically diverse bacteria. Due to a lack of molecular genetic tools, the mechanistic diversity of magnetosome formation remains poorly understood.Desulfovibrio magneticusRS-1 is an anaerobic sulfate-reducing Deltaproteobacterium that forms bullet-shaped magnetite crystals. A recent forward genetic screen identified ten genes in the conserved magnetosome gene island ofD. magneticusthat are essential for its magnetic phenotype. However, this screen likely missed many interesting mutants with defects in crystal size, shape, and arrangement. Reverse genetics to target the remaining putative magnetosome genes using standard genetic methods of suicide vector integration has not been feasible due to low transconjugation efficiency. Here, we present a reverse genetic method for targeted mutagenesis inD. magneticususing a replicative plasmid. To test this method, we generated a mutant resistant to 5-fluorouracil by making a markerless deletion of theuppgene that encodes uracil phosphoribosyltransferase. We also used this method for targeted marker exchange mutagenesis by replacingkupM,a gene identified in our previous screen as a magnetosome formation factor, with a streptomycin resistance cassette. Overall, our results show that targeted mutagenesis using a replicative plasmid is effective inD. magneticusand may also be applied to other genetically recalcitrant bacteria.

IMPORTANCE

Magnetotactic bacteria (MTB) are a group of organisms that form small, intracellular magnetic crystals though a complex process involving lipid and protein scaffolds. These magnetic crystals and their lipid membrane, termed magnetosomes, are model systems for studying bacterial cell biology and biomineralization as well as potential platforms for biotechnological applications. Due to a lack of genetic tools and unculturable representatives, the mechanisms of magnetosome formation in phylogenetically deeply-branching MTB remain unknown. These MTB contain elongated bullet-/tooth-shaped magnetite and greigite crystals that likely form in a manner distinct from the cubooctahedral-shaped magnetite crystals of the genetically tractable Alphaproteobacteria MTB. Here, we present a method for genome editing in the anaerobic DeltaproteobacteriumDesulfovibrio magneticusRS-1, the first cultured representative of the deeply-branching MTB. This marks a crucial step in developingD. magneticusas a model for studying diverse mechanisms of magnetic particle formation by MTB.
Point of care influenza testing using Alere-i Influenza A & B assay: a practical assessment
Authors: Blackmore Timothy K , Taylor James , Kelly Matthew , Buckley Jessica , Corban Karen , Tan Chor-Ee , Balm Michelle
Published: July 2018

We assessed the utility of the Alere i Influenza A & B point of care influenza test (Ai-POCIT) with laboratory testing using RT-PCR. 270 adult hospital patients had both Ai-POCIT and laboratory influenza tests conducted on the same sample. Overall, 30% and 32% influenza tests were positive by Ai-POCIT and RT-PCR, respectively. The sensitivity of the Ai-POCIT for influenza A, influenza B and any influenza were 93%, 100%, and 95%, respectively. Specificity was 100% for both viruses, but an 11% test failure rate indicates the need for better training of users. We believe that the use of nasopharyngeal (NP) swabs resulted in the observed high performance of the Ai-POCIT in comparison to other published studies. Ai-POCIT was regarded as very useful by front line clinical staff for clinical decision making and acute bed management.
AKT regulates mitotic progression of mammalian cells by phosphorylating MASTL
Authors: Reshi Irfana , Nisa Misbah Un , Farooq Umer , Gillani Syed Qaaifah , Bhat Sameer Ahmad , Sarwar Zarka , Fazili Khalid Majid , Andrabi Shaida
Published: July 2018

Microtubule associated serine threonine like kinase (MASTL) has been recently identified as an important regulator of mitosis. By inhibiting protein phosphatase 2A, it plays a crucial role in activating one of the most important mitotic kinases known as cyclin dependent kinase1 (CDK1). MASTL has been seen to be up regulated in various types of cancers and is involved in tumor recurrence. It is activated by CDK1 through its auto regulatory loop but the complete mechanism of its activation is still unclear. In this study, we evaluated the regulation of MASTL via AKT during mitosis. Here we report that AKT phosphorylates MASTL at T299 which plays a critical role in its activation. Our results suggest that AKT increases CDK1 mediated phosphorylation and hence activity of MASTL which in turn promotes cell proliferation.. We also show that the oncogenic potential of AKT is augmented by MASTL activation as the AKT mediated oncogenesis in colorectal cell lines can be attenuated by inhibiting and/or silencing MASTL. In brief, we report that AKT has an important role in the progression of mitosis in mammalian cells and it does so through the phosphorylation and activation of MASTL.
Polygenic predictors of age-related decline in cognitive ability
Authors: Ritchie Stuart J. , Hill W. David , Marioni Riccardo E. , Davies Gail , Hagenaars Saskia P. , Harris Sarah E. , Cox Simon R. , Taylor Adele M. , Corley Janie , Pattie Alison , Redmond Paul , Starr John M. , Deary Ian J.
Published: July 2018

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and environmental factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70 and cognitive change from age 70 to age 79 in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within old age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initialn= 1,091 age 70; finaln= 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We also ran an additional analysis using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardizedβ-values = –178 to .264), and the score for education was associated with cognitive change from childhood to age 70 (standardized = .102). None was statistically significantly associated with variation in cognitive change between ages 70 and 79.APOEe4 status made a significant prediction of cognitive decline from age 70 to 79 (standardizedβ= –319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par withAPOEe4, a more well-established predictor.
Dengue virus infection changesAedes aegyptioviposition olfactory preferences
Authors: Gaburro Julie , Paradkar Prasad N , Klein Melissa , Bhatti Asim , Nahavandi Saeid , Duchemin Jean-Bernard
Published: July 2018

Aedes aegyptimosquitoes, main vectors for numerous flaviviruses, have olfactory preferences and are capable of olfactory learning especially when seeking their required environmental conditions to lay their eggs. In this study, we showed that semiochemical conditions duringAedes aegyptilarval rearing affected future female choice for oviposition: water-reared mosquitoes preferred to lay eggs in water or p-cresol containers, while skatole reared mosquitoes preferred skatole sites. Using two independent behavioural assays, we showed that this skatole preference was lost in mosquitoes infected with dengue virus. Viral RNA was extracted from infected female mosquito heads, and an increase of virus load was detected from 3 to 10 days post infection, indicating replication in the insect head and possibly in the central nervous system. Expression of selected genes, potentially implied in olfactory learning processes, were also altered during dengue infection. Based on these results, we hypothesise that dengue virus infection alters gene expression in the mosquito’s head and is associated with a loss of olfactory preferences, possibly modifying oviposition site choice of female mosquitoes.
APP-induced patterned neurodegeneration exacerbated byAPOE4inC. elegans
Authors: Sae-Lee Wisath , Scott Luisa L. , Encarnacion Aliyah J. , Kore Pragati , Oyibo Lashaun O. , Ye Congxi , Pierce Jonathan T.
Published: July 2018

Genetic and epidemiological studies have found that variations in the amyloid precursor protein (APP) and the apoliopoprotein E (APOE) genes represent major modifiers of the progressive neurodegeneration in Alzheimer’s disease (AD). An extra copy or gain-of-function mutations inAPPlower age of AD onset. Compared to the other isoforms (APOE3andAPOE2), the ε4 allele ofAPOE(APOE4) hastens and exacerbates early and late onset forms of AD. Convenientin vivomodels to study how APP and APOE4 interact at the cellular and molecular level to influence neurodegeneration are lacking. Here, we show that the nematodeC. eleganscan model important aspects of AD including age-related, patterned neurodegeneration that is exacerbated byAPOE4. Specifically, we found thatAPOE4, but notAPOE3, acts withAPPto hasten and expand the pattern of cholinergic neurodegeneration caused byAPP. Molecular mechanisms underlying how APP and APOE4 synergize to kill some neurons while leaving others unaffected may be uncovered using this convenient worm model of neurodegeneration.
Endoreduplication inDrosophila melanogasterprogeny after exposure to acute γ-irradiation
Authors: Skorobagatko Daria A. , Mazilov Alexey A. , Strashnyuk Volodymyr Yu.
Published: July 2018

The purpose of investigation was to study the effect of acute γ-irradiation of parent adults on the endoreduplication inDrosophila melanogasterprogeny. As a material usedOregon-Rstrain. Virgin females and males ofDrosophilaadults at the age of 3 days were exposed at the doses of 8, 16 and 25 Gy. Giant chromosomes were studied at late 3rd instar larvae by cytomorphometric method. The average polyteny in males increased at the dose of 8 Gy by 10.6%, at the dose of 25 Gy by 7.4%, and did not change at the dose of 16 Gy. In females, the polyteny did not differ from the control value irrespective of the irradiation dose. The statistical impact power of sex on polyteny was 4,9%, the radiation impact was 26,8%. The enhancement of endoruplication is considered as a consequence of an increasing selection pressure after irradiation.
Similarities and differences in the crystal packing of halogen-substituted indole derivatives
Authors: Shukla Rahul , Singh Paramveer , Panini Piyush , Chopra Deepak
Published: July 2018

The role of different intermolecular interactions in the crystal structures of halogen-substituted indoles which are fused with six-membered or seven-membered cyclic rings is investigated here. Several crystal structures show isostructural characteristics due to the presence of similar supramolecular motifs. In the absence of any strong hydrogen bonds, the molecular packing of reported structures is primarily stabilized by the presence of non-classical N—H...π and C—H...π interactions in addition to C—H...X(X= F/Cl/Br) interactions. The nature and energetics of primary and secondary dimeric motifs are partitioned into the electrostatics, polarization, dispersion and exchange–repulsion components using the PIXEL method. Short and directional N—H...π interactions are further explored by a topological analysis of the electron density based on quantum theory of atoms in molecules.