bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of Serum Folic Acid and Homocysteine in Thalassemia Major Patients Before and After Folic Acid Supplement Cessation
Authors: Baghersalimi Adel , Hemmati Kolachahi Hajar , Darbandi Bahram , Kamran Mavardiani Zahra , Alizadeh Alinodehi Maryam , Dalili Setila , Hassanzadeh Rad Afagh
Published: August 2018

Background:

Thalassemic patients have ineffective erythropoiesis. In recent treatment protocols, there are little data on folic acid supplementation for patients with thalassemia because it is supposed that regular blood transfusions prevent bone marrow hyperfunctioning.

Objective:

Investigators aimed to assess serum folic acid and homocysteine (Hcy) in thalassemia major patients before and after folic acid supplement cessation.

Patients and Methods:

This study was a before-after controlled clinical trial conducted in 17th Shahrivar Hospital, Rasht, North of Iran, during May to October 2016. The patients enrolled in this study had thalassemia major on regular blood transfusion and older than 2 years of age. They had at least a 6-month history of folic acid supplement consumption before enrollment in the study (1 mg/daily). Complete blood count, serum folic acid, and serum Hcy were measured before discontinuation of folic acid supplement. Then, patients did not receive folic acid for a month and after 1 month of folic acid cessation, the measurements were repeated. All data were entered in SPSS version 20.0 and analyzed.

Results:

Among the 40 patients in this study, 25 (62.5%) were female. The mean age of the participants was 21.39±11.17 years old. The mean of body mass index was 21.38±3.32 kg/m2. Most of the participants had used folic acid supplement >5 years (29, 72.5%). The serum Hcy level was significantly increased (5.24±2.35 vs. 5.93±2.56; P=0.008) and serum folic acid level was decreased significantly (14.74±4.20 vs. 8.80±4.16; P<0.0001) from baseline.

Conclusions:

Cessation of folic acid supplementations in beta thalassemia major patients can lead to a significant decrease in serum folic acid and increase in Hcy levels. According to our findings and efficacy of folic acid in patients with beta thalassemia major, it is recommended to use the supplementation in all patients.
The Influence of Psychological Capital and Work Engagement on Intention to Remain of New Graduate Nurses
Authors: Kim Kyoung Ja , Yoo Moon Sook
Published: August 2018

OBJECTIVE

The aim of this study was to explore the influence of new graduate nurses' psychological capital (PsyCap) and work engagement (WE) on their intention to remain in nursing.

BACKGROUND

New graduate nurses experience stressful work environments, emotional exhaustion, and burnout. Positive psychological resources, such as PsyCap and WE, may promote the retention of new graduate nurses.

METHODS

A cross-sectional survey design was used. A structured questionnaire was answered by 156 new graduate nurses working at 2 tertiary hospitals and 1 university hospital in South Korea.

RESULTS

The intention to remain among new graduate nurses was correlated significantly with PsyCap and WE. A hierarchical regression of intention to remain against general characteristics, PsyCap, and WE explained 33.5% of intention to remain of new graduate nurses. Psychological capital and WE were influential in new graduate nurses' intention to remain.

CONCLUSIONS

Organizational attention is needed to foster PsyCap and WE to strengthen new graduate nurses' intention to remain in nursing.
Aerobic Training in Canadian Stroke Rehabilitation Programs
Authors: Nathoo Celine , Buren Shawna , El-Haddad Roni , Feldman Kaylee , Schroeder Erika , Brooks Dina , Inness Elizabeth L. , Marzolini Susan
Published: August 2018

Background and Purpose:

Aerobic training (AT) is recommended for people after stroke, yet uptake and operationalization of AT in clinical practice in Canada have not been measured. We surveyed inclusion of structured AT and barriers to implementation in public inpatient/outpatient stroke rehabilitation programs across Canada.

Methods:

A Web-based questionnaire was sent to 89 stroke rehabilitation program leads.

Results:

Forty-six programs from 7 of 9 eligible Canadian provinces/territories completed the questionnaire. Seventy-eight percent of programs reported including AT, with most (75%) excluding participants with severe physical impairments, and 28% excluding those with coexisting cardiac conditions. A greater proportion of dedicated stroke rehabilitation programs prescribed AT, compared to nondedicated stroke units (68.8% vs 31.3%, P = 0.02). The top 2 challenges for programs that included and did not include AT were “insufficient time within therapy sessions” and “length of stay in rehabilitation.” Programs that did not include AT ranked “not a goal of most patients” and “not an organizational/program priority” as third and fourth, whereas they were ranked eighth and thirteenth by programs with AT. Best practice recommendations were inconsistently followed for conducting preparticipation exercise testing (36.1%) and for monitoring patients from higher-risk populations, specifically people with diabetes at risk for hypoglycemia (78.8%) and hypertension (36.6%). Of programs conducting preparticipation exercise testing, 91% did not monitor electrocardiography.

Discussion and Conclusions:

Most stroke rehabilitation programs across Canada include AT. People with severe physical impairment and those with cardiac, metabolic, and hemodynamic comorbidities may be excluded or not appropriately monitored during exercise. More detailed guidelines and training practices are needed to address these challenges.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A233).
“Pancreatic Mucoepidermoid Carcinoma” Is not a Pancreatic Counterpart of CRTC1/3-MAML2 Fusion Gene-related Mucoepidermoid Carcinoma of the Salivary Gland, and May More Appropriately be Termed Pancreatic Adenosquamous Carcinoma With Mucoepidermoid Carcinoma-like Features
Authors: Saeki Kiyoshi , Ohishi Yoshihiro , Matsuda Ryota , Mochidome Naoki , Miyasaka Yoshihiro , Yamamoto Hidetaka , Koga Yutaka , Maehara Yoshihiko , Nakamura Masafumi , Oda Yoshinao
Published: August 2018

“Mucoepidermoid carcinoma (MEC)” has been accepted as a synonym for pancreatic adenosquamous carcinoma (ASC). Pancreatic ASC can show salivary gland-type MEC-like morphology. CRTC1/3-MAML2 fusion gene is a characteristic molecular feature of MEC of the salivary gland. We conducted this study to clarify whether the pancreatic ASC with salivary gland-type MEC-like morphology (Pan-MEC) is a pancreatic counterpart of salivary gland-type MEC (Sal-MEC). We retrospectively analyzed 37 pancreatic ASCs including 16 Pan-MECs and 21 tumors without MEC-like features (ASC-NOS [not otherwise specified]), and we investigated (1) clinicopathologic features, (2) the presence of CRTC1/3-MAML2 fusion gene by reverse transcription polymerase chain reaction, (3) the presence of rearrangement of MAML2 gene by fluorescence in situ hybridization, and (4) mucin core proteins by immunohistochemistry. We also compared 16 Pan-MECs with 20 Sal-MECs by immunohistochemistry for mucin core protein. There were no significant differences of any clinicopathologic characteristics and survival analysis between the Pan-MECs and ASCs-NOS. Of note, the pancreatic ASCs (including Pan-MEC and ASC-NOS) were significantly more aggressive than conventional pancreatic ductal adenocarcinoma. In addition, all Pan-MECs were histologically high-grade. CRTC1/3-MAML2 fusion gene and MAML2 gene rearrangement were not detected in any ASCs including Pan-MECs. There were significant differences of MUC5AC and MUC6 between the Pan-MECs and Sal-MECs, but no significant differences of mucin core protein between the Pan-MECs and pancreatic ASCs-NOS. Pan-MEC is histologically and biologically high-grade and unrelated to CRTC1/3-MAML2 fusion gene, unlike Sal-MEC which is related to CRTC1/3-MAML2 fusion gene. Pan-MEC is not a pancreatic counterpart of CRTC1/3-MAML2 fusion gene-related Sal-MEC.
The Incidence of Physiatry-Relevant Complications in Trauma Patients Admitted to an Urban Canadian Trauma Center
Authors: MacDonald Shannon L. , Robinson Lawrence R.
Published: August 2018

The objective of this study was to describe the incidence of complications in trauma patients that could be prevented, diagnosed, or managed by a consulting acute care physiatrist. Demographic and complication data were extracted by chart review of adult trauma patients admitted to a Canadian academic trauma center. Subjects were included if they had a diagnosis of traumatic brain injury, spinal cord injury, or multiple injuries resulting in an Injury Severity Score greater than 15. Means and standard deviations were calculated for continuous variables and frequencies for categorical data. Secondary analyses involved using Spearman's ρ and χ2 analysis to examine relationships between the development of complications and various patient factors. A total of 286 individuals were included. The overall incidence of a physical medicine & rehabilitation-relevant complication was 32.9%. The complications with the highest incidence were pneumonia (15.5%), delirium (14.1%), and urinary tract infection (13.4%). Secondary analyses demonstrated associations between the development of complications with older age, the presence of comorbidities, having both a traumatic brain injury and spinal cord injury, and length of stay. This study demonstrated that trauma patients may experience multiple complications that are of relevance to the consulting physiatrist.
A Current Review of Biologic Meshes in Abdominal Wall Reconstruction
Authors: Nahabedian Maurice Y. , Sosin Michael , Bhanot Parag
Published: August 2018

It is well accepted that the use of mesh has facilitated and improved outcomes following repair of the complex abdominal hernias. Current mesh options include biologic, synthetic, and resorbable materials. The use of biologic materials for the repair and reinforcement of abdominal wall hernia has generated significant discussion. There are a variety of biologic mesh materials that are currently available that are derived from various sources including human, porcine, or bovine. All are processed for heterogeneous use, include variable amounts of collagen and elastin, and may or may not be crosslinked. The mechanism of action for biologic mesh is the incorporation, revascularization, and recellularization into the surrounding soft tissue. The presumed benefit is that the added soft-tissue support will reduce the incidence of surgical-site occurrences including recurrence. This article will review the salient studies that have incorporated biologic materials for the repair of complex abdominal hernia.
Enhanced Recovery Pathway for Complex Abdominal Wall Reconstruction
Authors: Orenstein Sean B. , Martindale Robert G.
Published: August 2018

Ventral hernia repair with abdominal wall reconstruction can be a challenging endeavor, as patients commonly present not only with complex and recurrent hernias but also often with comorbidities that increase the risk of postoperative complications including wound morbidity and hernia recurrence, among other risks. By optimizing patient comorbidities in the preoperative setting and managing postoperative care in a regimented fashion, enhanced recovery after surgery pathways allow for a systematic approach to reduce complications and speed up recovery following ventral hernia repair.
Measuring Success in Complex Abdominal Wall Reconstruction: The Role of Validated Outcome Scales
Authors: Otero Javier , Arnold Michael R. , Hope William W. , Augenstein Vedra A.
Published: August 2018

Background:

Diminished quality of life (QOL) often drives patients to hernia repair, and patient-reported outcomes have gained importance in hernia research. Functional outcomes provide a patient-centered evaluation of a treatment, and improved QOL is a desired outcome assessing treatment effectiveness.

Methods:

Properties of validated QOL measure are reviewed and distinctions between generic and disease-specific measures are discussed. Based on a review of the literature, current validated outcome scales are evaluated and compared.

Results:

Currently, there is little agreement over the best means to measure QOL. As a result, several measures have been created, focusing on several distinct aspects of QOL. While generic measures provide global assessments, disease-specific measures report changes as they relate to the hernia itself and hernia surgery. With the introduction of new QOL measures, it is important to understand the properties of a good QOL measure.

Conclusions:

Several questions remain unanswered regarding QOL, including which measures best assess hernia patients, what is the ideal time to evaluate QOL, and for how long postoperatively should QOL be measured. The introduction of guidelines to address these issues may enable improvement in value assessment.
Factors Associated With Progression of Lung Function Abnormalities in HIV-Infected Individuals
Authors: Li Yijia , Nouraie Seyed Mehdi , Kessinger Cathy , Weinman Renee , Huang Laurence , Greenblatt Ruth M. , Kleerup Eric , Kingsley Lawrence , McMahon Deborah , Fitzpatrick Meghan , Morris Alison
Published: August 2018

Background:

HIV is an independent risk factor for chronic obstructive pulmonary disease; however, baseline risk factors for lung function decline remain largely unknown in this population.

Methods:

HIV-infected participants in the Pittsburgh Lung HIV Cohort with at least 3 pulmonary function measurements between 2007 and 2016 were included. Pulmonary function testing including postbronchodilator (BD) spirometry and diffusion capacity for carbon monoxide (DLco) was performed every 18 months. We used a mixed-effect linear model to evaluate factors associated with pulmonary function testing and DLco decline and logistic regression models to evaluate factors associated with rapid FEV1 decline (defined as >80 mL per year) and any DLco decline.

Results:

Two hundred eighty-five HIV-infected participants were included. Median baseline CD4 cell count was 521 cells per micro liter, 61.9% had an undetectable HIV viral load at baseline, and 78.5% were receiving ART. Approximately 20% of participants met Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for a diagnosis of chronic obstructive pulmonary disease at baseline. Older age and baseline GOLD stage 1 compared with stage 0 were associated with faster decline in post-BD FEV1%, whereas female sex was associated with slower decline. Similarly, female sex was associated with slower decline in DLco%. HIV-related factors including CD4 cell count, viral load, and ART use were not significantly associated with pulmonary function decline.

Conclusions:

Older age, male sex, and higher baseline GOLD stage were associated with more rapid post-BD FEV1% decline in HIV-infected individuals.
Typhoid and paratyphoid fever: a call to action
Authors: Gibani Malick M. , Britto Carl , Pollard Andrew J.
Published: August 2018

Purpose of review

Enteric fever remains a major global-health concern, estimated to be responsible for between 11.9 and 26.9 million cases annually. Long-term prevention of enteric fever will require improved access to safe drinking water combined with investment in sanitation and hygiene interventions. In the short-to-medium term, new control strategies for typhoid fever have arrived in the form of typhoid Vi-conjugate vaccines (TCVs), offering hope that disease control can be achieved in the near future.

Recent findings

The diagnosis of enteric fever is complicated by its nonspecific clinical presentation, coupled with the low sensitivity of commonly used diagnostics. Investment in diagnostics has the potential to improve management, to refine estimates of disease burden and to facilitate vaccine impact studies. A new generation of reliable, diagnostic tests is needed that are simultaneously accessible, cost-effective, sensitive, and specific. The emergence and global dissemination of multidrug-resistant, fluoroquinolone-resistant, and extensively drug-resistant (XDR) strains of Salmonella Typhi emphasizes the importance of continued surveillance and appropriate antibiotic stewardship, integrated into a global strategy to address antimicrobial resistance (AMR). Current empirical treatment guidelines are out of date and should be updated to respond to local trends in AMR, so as to guide treatment choices in the absence of robust diagnostics and laboratory facilities. In September 2017, the WHO Strategic Advisory Group of Experts (SAGE) immunization recommended the programmatic use of TCVs in high burden countries. Ongoing and future studies should aim to study the impact of these vaccines in a diverse range of setting and to support the deployment of TCVs in high-burden countries.

The advent of new generation TCVs offers us a practical and affordable public-health tool that – for the first time – can be integrated into routine childhood immunization programmes. In this review, we advocate for the deployment of TCVs in line with WHO recommendations, to improve child health and limit the spread of antibiotic-resistant S. Typhi.
Cowden Syndrome
Authors: Parvinian Ahmad , Cox Christian W. , Hartman Thomas E.
Published: August 2018

Objective:

To describe the pulmonary imaging findings in patients with Cowden syndrome (CS).

Materials and Methods:

A retrospective review identified all patients with CS who underwent dedicated computed tomography examinations of the chest at our institution between January 2000 and October 2017. Patient demographics and imaging characteristics were identified through a review of the electronic medical record and relevant imaging.

Results:

Fifteen patients (6 males/9 females; mean age 53 y) with a clinical diagnosis of CS were identified. Genetic confirmation of the PTEN mutation was available in 8/15 (50%) patients. Pulmonary cysts were present in 12/15 (80%) patients and in 8/8 (100%) patients with documented PTEN mutations. The cysts ranged in size from 4 to 63 mm and were <10 in 10/12 (83%). Cysts were distributed randomly in 10/12 (83%) cases. Solid pulmonary nodules were present in 13/15 (87%) patients and were distributed randomly in all cases.

Conclusions:

Pulmonary cysts and solid nodules are common in patients with CS. Cysts tend to be distributed randomly, few in number, and may have traversing vessels. These findings should not be interpreted as evidence of another underlying disorder in the setting of CS.
Radiologist Performance in the Detection of Pulmonary Embolism
Authors: Kligerman Seth J. , Mitchell Jason W. , Sechrist Jacob W. , Meeks Adam K. , Galvin Jeffrey R. , White Charles S.
Published: August 2018

Purpose:

This study aimed to assess the factors contributing toward accurate detection and erroneous interpretation of pulmonary embolism (PE).

Materials and Methods:

Over 13 months, all computed tomography pulmonary angiography studies were retrospectively rereviewed by a chest radiologist. Two additional chest radiologists assessed cases with disagreement between the first interpretation and rereview. The number, extent, and location of PE and specialty training, experience, time of study, kV, resident prelim, use of iterative reconstruction, signal to noise ratio (SNR), and reports describing the study as “limited” were recorded. Parametric and nonparametric statistical testing was performed (significance P<0.05).

Results:

Of 2555 computed tomography pulmonary angiography cases assessed, there were 230 true positive (170 multiple, 60 single PE), 2271 true negative, 35 false-negative (15 multiple and 20 single PE), and 19 false-positive studies. The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy of radiologists was 86.8%, 99.2%, 92.4%, 98.5%, and 97.9%. Sensitivity for the detection of multiple and central PE was significantly higher than the detection of single and peripheral PE, respectively (P<0.01 for both). The sensitivity of thoracic radiologists (91.7%) was higher than nonthoracic (82.8%) and reached significance for single PE (89.2% vs. 61.4%, P<0.02). Errors were more likely in cases with lower SNR (P=0.04) and those described as limited (P<0.001). Misses occurred more frequently in the upper lobe posterior and lower lobe lateral segments and subsegments (P=0.038).

Conclusions:

The accuracy for PE detection is high, but errors are more likely in studies with single PE interpreted by nonthoracic radiologists, especially when located in certain segments and in cases with low SNR or described as limited.
Salmonella infection – prevention and treatment by antibiotics and probiotic yeasts: a review
Authors: Gut Abraham Majak , Vasiljevic Todor , Yeager Thomas , Donkor Osaana N.
Published: August 2018

Global Salmonella infection, especially in developing countries, is a health and economic burden. The use of antibiotic drugs in treating the infection is proving less effective due to the alarming rise of antibiotic-resistant strains of Salmonella, the effects of antibiotics on normal gut microflora and antibiotic-associated diarrhoea, all of which bring a growing need for alternative treatments, including the use of probiotic micro-organisms. However, there are issues with probiotics, including their potential to be opportunistic pathogens and antibiotic-resistant carriers, and their antibiotic susceptibility if used as complementary therapy. Clinical trials, animal trials and in vitro investigations into the prophylactic and therapeutic efficacies of probiotics have demonstrated antagonistic properties against Salmonella and other enteropathogenic bacteria. Nonetheless, there is a need for further studies into the potential mechanisms, efficacy and mode of delivery of yeast probiotics in Salmonella infections. This review discusses Salmonella infections and treatment using antibiotics and probiotics.
Different neural networks for conceptual retrieval in sighted and blind
Authors: Bottini Roberto , Ferraro Stefania , Nigri Anna , Cuccarini Valeria , Bruzzone Maria Grazia , Collignon Olivier
Published: August 2018

We investigated the experiential bases of knowledge by asking whether people that perceive the world in a different way also show a different neurobiology of concepts. We characterized the brain activity of early-blind and sighted individuals during a conceptual retrieval task in which participants rated the perceptual similarity between color and action concepts evoked by spoken words. Adaptation analysis showed that word-pairs referring to perceptually similar colors (e.g., red-orange) or actions (e.g., run-jump) led to repetition-suppression in occipital visual regions in the sighted, regions that are known to encode visual features of objects and events, independently of their category. Early blind showed instead adaptation for similar concepts in language-related regions, but not in occipital cortices. Further analysis contrasting the two categories (color and action), independently of item similarity, activated category-sensitive regions in the pMTG (for actions) and the precuneus (for color) in both sighted and blind. These two regions, however, showed a different connectivity profile as a function of visual deprivation, increasing task-dependent connectivity with reorganized occipital regions in the early blind. Overall, our results show that visual deprivation changes the neural bases of conceptual retrieval, which is partially grounded in sensorimotor experience.

Significance Statement

Do people with different sensory experience conceive the world differently? We tested whether conceptual knowledge builds on sensory experience by looking at the neurobiology of concepts in early blind individuals. Participants in fMRI heard pairs of words referring to colors (e.g., green-blue) or actions (e.g., jump-run) and rated their perceptual similarity. Perceptual similarity of colors and actions was represented in occipital visual regions in the sighted, but in language-related regions in the blind. Occipital regions in the blind, albeit not encoding perceptual similarity, were however recruited during conceptual retrieval, working in concert with classic semantic hubs such as the Precuneus and the lpMTG. Overall, visual deprivation changes the neural bases of conceptual processing, which is partially grounded in sensorimotor experience.
Herd protection against Plasmodium falciparum infections conferred by mass antimalarial drug administrations and the implications for malaria elimination
Authors: Parker Daniel M. , Than Tun Sai Thein , White Lisa J. , Kajeechiwa Ladda , Thwin May Myo , Landier Jordi , Chaumeau Victor , Corbel Vincent , Dondorp Arjen M. , Seidlein Lorenz von , White Nicholas J. , Maude Richard J. , Nosten François H.
Published: August 2018

The global malaria burden has decreased over the last decade and many nations are attempting elimination. Asymptomatic infections aren’t normally diagnosed or treated, posing a major hurdle for elimination efforts. One solution to this problem is mass drug administration (MDA), which is dependent on adequate population participation to disrupt transmission. There is little empirical evidence regarding the necessary threshold level of participation. Here we present a detailed spatiotemporal analysis of malaria episodes and asymptomatic infections in four villages undergoing MDA in Myanmar. Individuals from neighborhoods with high MDA adherence had 90% decreased odds of having a malaria episode post-MDA, regardless of individual participation, suggesting a strong herd effect. High mosquito biting rates, living in a house with someone else with malaria, or having an asymptomatic malaria infection were also predictors of clinical episodes. Spatial clustering of non-adherence to MDA, even in villages with high overall participation, can frustrate elimination efforts.
Mesenchymal stem cells protect retinal ganglion cells from degeneration via mitochondrial donation
Authors: Jiang Dan , Feng Hong , Zhang Zhao , Yan Bin , Chen Ling , Ma Chuiyan , Li Cheng , Han Shuo , Zhang Yuelin , Chen Peikai , Tse Hung-Fat , Fu Qingling , Chiu Kin , Lian Qizhou
Published: August 2018

Retinal ganglion cell (RGC) degeneration is extremely hard to repair or regenerate and is often coupled with mitochondrial dysfunction. Mesenchymal stem cells (MSCs)-based treatment has been demonstrated beneficial for RGC against degeneration. However, underlying mechanisms of MSC-provided RGC protection are largely unknown other than neuropectective paracrine actions. In this study, we sought to investigate whether mitochondrial donation can preserve RGC functions, in a mitochondrialNdufs4deficient mouse model of RGC degeneration. The results revealed intravitreal transplanted by induced pluripotent stem cell derived-MSCs (iPSC-MSC) could donate their mitochondria through crossing inner limited membrane to host RGCs. Furthermore, the donated mitochondria effectively protected against RGC death and largely preserved retinal function inNdufs4-KO mice. Importantly, the protective effects of mitochondrial donation from MSCs were associated with management of pro-inflammatory cytokines. Our data identified a novel role of MSCs-mitochondrial donation in protection of RGC from degeneration, and highlight a viable therapeutic strategy by manipulating stem cell mitochondrial donation for the treatment of retina degeneration in future.
Structural Basis of Broad Ebolavirus Neutralization by a Human Survivor Antibody
Authors: West Brandyn R. , Wec Anna Z. , Moyer Crystal L. , Fusco Marnie L. , Ilinykh Phillipp A. , Huang Kai , James Rebekah M. , Herbert Andrew S. , Hui Sean , Wirchnianski Ariel S. , Goodwin Eileen , Javad Aman M. , Walker Laura M. , Dye John M. , Bukreyev Alexander , Chandran Kartik , Saphire Erica Ollmann
Published: August 2018

The structural features that govern broad-spectrum activity of broadly neutralizing, anti-ebolavirus antibodies (Abs) are currently unknown. Here we describe the first structure of a broadly neutralizing human Ab, ADI-15946, in complex with cleaved Ebola virus glycoprotein (EBOV GPCL). We find that ADI-15946 employs structural mimicry of a conserved interaction between the GP core and the glycan cap β17-β18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of monoclonal Ab (mAb) FVM09 displace this loop, increase exposure of ADI-15946’s conserved epitope and potentiate neutralization. Our work also illuminated the determinants of ADI-15946’s reduced activity against Sudan virus (SUDV), and enabled rational, structure-guided engineering to enhance binding and neutralization against SUDV while retaining the parental breadth of activity.

One Sentence Summary

The first crystal structure of a broadly active antibody against surface glycoproteins of ebolaviruses identifies a highly conserved epitope beneath the glycan cap and highlights the molecular requirements for broad ebolavirus neutralization.
Variations in the phagosomal environment of human neutrophils and mononuclear phagocyte subsets
Authors: Foote Juliet R. , Patel Amit A. , Yona Simon , Segal Anthony W.
Published: August 2018

The phagosomal microenvironment has a major influence on the enzyme activity and biology within these organelles. Here we directly compared the phagosomal pH of human neutrophils, monocytes, dendritic cell (DC) and monocyte-derived cells. An unexpected observation was the striking difference in phagosomal environment between the three monocytes subsets. Classical monocytes and neutrophils had alkaline phagosomes, yet non-classical monocytes had more acid phagosomes. Intermediate monocytes had an intermediate phenotype. We next investigated the differences between primary DCs versusin vitromonocyte-derived DCs and established that both these cells had acidic phagosomal environments. We also confirmed reports of an alkaline phagosome in “M1” macrophages, and an acidic one in “M2” macrophages. Across all phagocytes, alkalinisation was dependent upon the activity of the NADPH oxidase, as when it was absent in cells from a patient with chronic granulomatous disease (CGD) or was abolished by an inhibitor of the oxidase, diphenyleneiodonium (DPI). An increased alkalinity in the phagosome was associated with more oxidase activity. These data highlight the heterogenous nature of phagocytic vacuoles within the family of mononuclear phagocytes that will dictate the function of these compartments.

Key points

Phagosomal function depends upon the action of enzymes released into them from cytoplasmic granules.

The substantial differences in the phagosomal pH in the different phagocytes will affect their compliment of enzymes and their functions.
Genomic Surveillance for Antimicrobial Resistance inMannheimia haemolyticaUsing Nanopore Single Molecule Sequencing Technology
Authors: Lim Alexander , Naidenov Bryan , Bates Haley , Willyerd Karyn , Snider Timothy , Couger Matthew Brian , Chen Charles , Ramachandran Akhilesh
Published: August 2018

Disruptive innovations in long-range, cost-effective direct template nucleic acid sequencing are transforming clinical and diagnostic medicine. A multidrug resistant strain and a pan-susceptible strain ofMannheimia haemolytica, isolated from pneumonic bovine lung samples, were respectively sequenced at 146x and 111x coverage with Oxford Nanopore Technologies MinION.De novoassembly produced a complete genome for the non-resistant strain and a nearly complete assembly for the drug resistant strain. Functional annotation using RAST (Rapid Annotations using Subsystems Technology), CARD (Comprehensive Antibiotic Resistance Database) and ResFinder databases identified genes conferring resistance to different classes of antibiotics including beta lactams, tetracyclines, lincosamides, phenicols, aminoglycosides, sulfonamides and macrolides. Antibiotic resistance phenotypes of theM. haemolyticastrains were confirmed with minimum inhibitory concentration (MIC) assays. The sequencing capacity of highly portable MinION devices was verified by sub-sampling sequencing reads; potential for antimicrobial resistance determined by identification of resistance genes in the draft assemblies with as little as 5,437 MinION reads corresponded to all classes of MIC assays. The resulting quality assemblies and AMR gene annotation highlight efficiency of ultra long-read, whole-genome sequencing (WGS) as a valuable tool in diagnostic veterinary medicine.
A simple chromogenic whole-cell arsenic biosensor based onBacillus subtilis
Authors: Wicke Niels , Radford David S. , French Christopher E.
Published: August 2018

Arsenic contaminated ground water is a serious public health issue, and recent estimates place 150 million people worldwide at risk. Current chemical field test kits do not reliably detect arsenic at the lower end of the relevant range, and may generate toxic intermediates and waste. Whole-cell biosensors potentially provide an inexpensive, robust and analyte-specific solution to this problem. The second generation of aBacillus subtilis-based arsenic biosensor, designated Bacillosensor-II, was constructed using the native chromosomalarspromoter,arsRand the reporter genexylEencoding catechol-2,3-dioxygenase. Within four hours, Bacillosensor-II can detect arsenic in the form of arsenate AsO43-at levels more than one order of magnitude below the recommended safe limit for drinking water suggested by the World Health Organisation (10 µg/L). Detection is reported by the enzymatic conversion of the inexpensive substrate catechol to 2-hydroxy-cis,cis-muconic semialdehyde, a bright yellow product visible by eye. We hope that this work will aid in developing a simple inexpensive field test kit for screening of drinking water for arsenic contamination.
Developmental Effects of the Pesticide Imidacloprid on Zebrafish Body Length and Mortality
Authors: Krishnan Akshay , Clyburn Christin , Newcombe Patrick
Published: August 2018

The pesticide imidacloprid, a Neonicotinoid, is widely used and commercially available. Neonicotinoids are antagonists at nicotinic acetylcholine receptors, which can cause neurobehavioral effects in developing organisms. While the effects of other insecticides such as Malathion and Fipronil on zebrafishDanio reriodevelopment have been studied, few studies describe the morphological effects of imidacloprid during zebrafish development. To test the hypothesis that imidacloprid concentration positively correlates to increased mortality and decreased body length, we exposed zebrafish to imidacloprid for five days post fertilization. Body length and embryo mortality were recorded at 1, 2, 3, 4, and 5 days post fertilization in 0 ug/L, 100 ug/L, 1,000 ug/L, and 10,000 ug/L imidacloprid concentrations. These concentrations were chosen to mimic levels that could be reached in the environment especially soon after application. Our results demonstrate statistically increased embryo mortality, with a f crit value of 3.193 and a f value of 3.098 from an ANOVA test, and impaired body length with a dose dependent correlation to the concentration of imidacloprid and a P value of less than 0.01 from a T test. Given the pesticide’s high prevalence, future studies should be considered to determine if this effect may impact livestock and human development.
Whole-neuron synaptic mapping reveals local balance between excitatory and inhibitory synapse organization
Authors: Iascone Daniel Maxim , Li Yujie , Sümbül Uygar , Doron Michael , Chen Hanbo , Andreu Valentine , Goudy Finola , Segev Idan , Peng Hanchuan , Polleux Franck
Published: August 2018

The balance between excitatory and inhibitory (E and I) synaptic inputs is thought to be critical for information processing in neural circuits. However, little is known about the principles of spatial organization of E and I synapses across the entire dendritic tree of mammalian neurons. We developed a new, open-source, reconstruction platform for mapping the size and spatial distribution of E and I synapses received by individual, genetically-labeled, layer 2/3 cortical pyramidal neurons (PNs) in vivo. We mapped over 90,000 E and I synapses across twelve L2/3 PNs and uncovered structured organization of E and I synapses across dendritic domains as well as within individual dendritic segments in these cells. Despite significant, domain-specific, variations in the absolute density of E and I synapses, their ratio is strikingly balanced locally across dendritic segments. Computational modeling indicates that this spatially-precise E/I balance dampens dendritic voltage fluctuations and strongly impacts neuronal firing output.
A Proof-of-Principle of Nanoscale Optogenetics
Authors: Stahlberg Markus A. , Ramakrishnan Charu , Willig Katrin I. , Boyden Edward S. , Deisseroth Karl , Dean Camin
Published: August 2018

Optogenetics has revolutionized the study of circuit function in the brain, by allowing activation of specific ensembles of neurons by light. However, this technique has not yet been exploited extensively at the subcellular level. Here we propose a novel focal stimulation approach using STED/RESOLFT-like illumination, whereby switchable light-gated channels are focally activated by a laser beam of one wavelength and deactivated by an overlapping donut-shaped beam of a different wavelength, confining activation to a center focal region. We demonstrate the utility of current optogenetic tools to achieve highly focal depolarization using this method and further examine a proof-of-principle of nanoscale optogenetic activation using an initial macroscale approach. When employed at the nanoscale, this approach will allow unprecedented optogenetic control of nanodomains within cells.
Molecular structure and function of myelin protein P0 in membrane stacking
Authors: Raasakka Arne , Ruskamo Salla , Kowal Julia , Han Huijong , Baumann Anne , Myllykoski Matti , Fasano Anna , Rossano Rocco , Riccio Paolo , Bürck Jochen , Ulrich Anne S. , Stahlberg Henning , Kursula Petri
Published: August 2018

Compact myelin forms the basis of nerve insulation essential for higher vertebrates. Dozens of myelin membrane bilayers undergo tight stacking, and in the peripheral nervous system, this is partially enabled by myelin protein zero (P0). Consisting of an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension (P0ct), P0 harbours an important task in ensuring the integrity of compact myelin in the extracellular compartment, referred to as the intraperiod line. Several disease mutations resulting in peripheral neuropathies have been identified for P0, reflecting its physiological importance, but the arrangement of P0 within the myelin ultrastructure remains obscure. We performed a biophysical characterization of recombinant P0ct. P0ct contributes to the binding affinity between apposed cytoplasmic myelin membrane leaflets, which not only results in fluidity changes of the bilayers themselves, but also potentially involves the rearrangement of the Ig-like domains in a manner that stabilizes the intraperiod line. Transmission electron cryomicroscopy of native full-length P0 showed that P0 stacks lipid membranes by forming antiparallel dimers between the extracellular Ig-like domains. The zipper-like arrangement of the P0 extracellular domains between two membranes explains the double structure of the myelin intraperiod line. Our results contribute to the understanding of PNS myelin, the role of P0 therein, and the underlying molecular foundation of compact myelin stability in health and disease.
Opposing effects of prostaglandin receptor EP2 signaling in mouse immune cells and neurons after status epilepticus
Authors: Varvel Nicholas H. , Chen Di , Biegel Ariel , Dingledine Raymond
Published: August 2018

A multidimensional inflammatory response ensues after status epilepticus (SE), driven partly by cyclooxygenase-2 mediated activation of prostaglandin EP2 receptors. Here we identify those effects of EP2 antagonism that are reproduced by conditional ablation of EP2 receptors in immune myeloid cells and forebrain neurons. Removal of myeloid cell EP2 dampened induction of hippocampal IL-6, prevented erosion of the blood-brain barrier, accelerated weight regain, and relieved ptosis following SE. Elimination of EP2 receptor from neurons enhanced neuronal injury, elevated hippocampal induction of the pro-inflammatory cytokines, TNFα and Ccl2, promoted deterioration of the blood-brain barrier, delayed weight recovery, and worsened animal posture and activity. Taken together these data highlight the complexities in neuroinflammatory signaling, wherein activation of EP2 receptors in innate immune cells is deleterious but neuronal EP2 signaling is protective. Effective treatments targeting brain prostaglandin signaling pathways should be cell targeted to be optimally effective.

Significance Statement

Seizures reduce quality of life, promote the development of epilepsy, and can be fatal. We previously identified inflammation, via prostaglandin receptor EP2 activation, as a driver of undesirable seizure-induced effects. However, the relevant EP2-expressing cell types remain unclear. We identify innate immune cells as a driver of the EP2-related negative consequences of seizures, whereas neuronal EP2 signaling is protective. Genetic removal of EP2 from immune cells was beneficial, accelerating weight gain and limiting behavioral deficits. Elimination of EP2 from neurons was harmful, worsening behavioral deficits and promoting neuronal damage. These findings enhance our understanding of the complex inflammatory processes engaged after seizures and will assist in the development of beneficial therapies to enhance quality of life in individuals susceptible to seizures.
Single cell RNA-seq study of wild type and Hox9,10,11 mutant developing uterus
Authors: Mucenski Michael L. , Mahoney Robert , Adam Mike , Potter Andrew S. , Potter S. Steven
Published: August 2018

The uterus is a remarkable organ that must guard against infections while maintaining the ability to support growth of a fetus without rejection. TheHoxa10andHoxa11genes have previously been shown to play essential roles in uterus development and function. In this report we show that theHoxc9,10,11genes play a redundant role in the formation of uterine glands. In addition, we use single cell RNA-seq to create a high resolution gene expression atlas of the developing wild type mouse uterus. Cell types and subtypes are defined, for example dividing endothelial cells into arterial, venous, capillary, and lymphatic, while epithelial cells separate into luminal and glandular subtypes. Further, a surprising heterogeneity of stromal and myocyte cell types are identified. Transcription factor codes and ligand/receptor interactions are characterized. We also used single cell RNA-seq to globally define the altered gene expression patterns in all developing uterus cell types for two Hox mutants, with 8 or 9 mutant Hox genes. The mutants show a striking disruption of Wnt signaling as well as the Cxcl12/Cxcr4 ligand/receptor axis.

Summary statement

A single cell RNA-seq study of the developing mouse uterus defines cellular heterogeneities, lineage specific gene expression programs and perturbed pathways in Hox9,10,11 mutants.
Transcriptome Analysis of Distinct Cold Tolerance Strategies in the Rubber Tree (Hevea brasiliensis)
Authors: Mantello Camila Campos , Boatwright Lucas , da Silva Carla Cristina , Scaloppi Erivaldo Jose , Souza Gonçalves Paulo de , Barbazuk W. Brad , de Souza Anete Pereira
Published: August 2018

Natural rubber is an indispensable commodity used in approximately 40,000 products and is fundamental to the tire industry. Among the species that produce latex, the rubber tree [Hevea brasiliensis (Willd. ex Adr. de Juss.) Muell-Arg.], a species native to the Amazon rainforest, is the major producer of latex used worldwide. The Amazon Basin presents optimal conditions for rubber tree growth, but the occurrence of South American leaf blight, which is caused by the fungus Microcyclus ulei (P. Henn) v. Arx, limits rubber tree production. Currently, rubber tree plantations are located in scape regions that exhibit suboptimal conditions such as high winds and cold temperatures. Rubber tree breeding programs aim to identify clones that are adapted to these stress conditions. However, rubber tree breeding is time-consuming, taking more than 20 years to develop a new variety. It is also expensive and requires large field areas. Thus, genetic studies could optimize field evaluations, thereby reducing the time and area required for these experiments. Transcriptome sequencing using next-generation sequencing (RNA-seq) is a powerful tool to identify a full set of transcripts and for evaluating gene expression in model and non-model species. In this study, we constructed a comprehensive transcriptome to evaluate the cold response strategies of the RRIM600 (cold-resistant) and GT1 (cold-tolerant) genotypes. Furthermore, we identified putative microsatellite (SSR) and single-nucleotide polymorphism (SNP) markers. Alternative splicing, which is an important mechanism for plant adaptation under abiotic stress, was further identified, providing an important database for further studies of cold tolerance.
Morphogenetic processes as data: Quantitative structure in theDrosophilaeye imaginal disc
Authors: Alicea Bradly , Portegys Thomas E. , Gordon Diana , Gordon Richard
Published: August 2018

We can improve our understanding of biological processes through the use of computational and mathematical modeling. One such morphogenetic process (ommatidia formation in theDrosophilaeye imaginal disc) provides us with an opportunity to demonstrate the power of this approach. We use a high-resolution image that catches the spatially- and temporally-dependent process of ommatidia formation in the act. This image is converted to quantitative measures and models that provide us with new information about the dynamics and geometry of this process. We approach this by addressing three computational hypotheses, and provide a publicly-available repository containing data and images for further analysis. Potential spatial patterns in the morphogenetic furrow and ommatidia are summarized, while the ommatidia cells are projected to a spherical map in order to identify higher-level spatiotemporal features. In the conclusion, we discuss the implications of our approach and findings for developmental complexity and biological theory.
Altitudinal range-size distribution of breeding birds and environmental factors for the determination of species richness: An empirical test of altitudinal Rapoport’s rule and rescue effect on a local scale
Authors: Kim Jin-Yong , Seo Changwan , Hong Seungbum , Lee Sanghoon , Eo Soo Hyung
Published: August 2018

Range-size distributions are important for understanding species richness patterns and led to the development of the controversial Rapoport’s rule and Rapoport-rescue effect. This study aimed to understand the relationship between species richness and range-size distribution in relation to environmental factors. The present study tested the following: (1) altitudinal Rapoport’s rule, (2) climatic and ambient energy hypotheses, (3) non-directional rescue effect, and (4) effect of environmental factors on range-size group. Altitudinal species range-size distribution increased with increasing altitude and showed a negative relationship with climatic variables and habitat heterogeneity, and a positive relationship with primary productivity. These results support the altitudinal Rapoport’s rule and climatic hypothesis; however, they do not fully support the ambient energy hypothesis. Results from testing the non-directional rescue effect showed that the inflow intensity of species from both directions (high and low elevations) affected species richness. And we found that the 2nd and 3rd quartile species distribution were the main cause of a mid-peak of species richness and the non-directional rescue effect. Additionally, the 2nd quartile species richness was highly related to minimum temperature and possessed thermal specialist species features, and the 3rd quartile species richness was highly related to habitat heterogeneity and primary productivity. Although altitudinal range-size distribution results were similar to the altitudinal Rapoport’s rule, the mid-peak pattern of species richness could not be explained by the Rapoport’s-rescue effect; however, the non-directional rescue effect could explain a mid-peak pattern of species richness.