bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Tenofovir-Based Pre-exposure Prophylaxis on Biomarkers of Bone Formation, Bone Resorption, and Bone Mineral Metabolism in HIV-Negative Adults
Authors: Nickolas Thomas L , Yin Michael T , Hong Ting , Mugwanya Kenneth K , Branch Andrea D , Heffron Renee , Ramalho Janaina , Nandakumar Renu , Dworakowski Elzbieta , Wanga Valentine , Mugo Nelly R , Ronald Allan , Celum Connie , Donnell Deborah , Baeten Jared M , Wyatt Christina M ,   Partners PrEP Study Team, Celum Connie , Baeten Jared M , Donnell Deborah , Coombs Robert W , Frenkel Lisa , Hendrix Craig W , Lingappa Jairam R , McElrath M Juliana , Fife Kenneth H , Were Edwin , Tumwesigye Elioda , Ndase Patrick , Katabira Elly , Ronald Allan , Bukusi Elizabeth , Cohen Craig R , Wangisi Jonathan , Campbell James D , Tappero Jordan W , Kiarie James , Farquhar Carey , John-Stewart Grace , Mugo Nelly R , Campbell James D , Tappero Jordan W , Wangisi Jonathan
Published: August 2019

Background

Pre-exposure prophylaxis (PrEP) with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) reduces the risk of HIV seroconversion but may promote bone mineral density (BMD) decline. The mechanisms of BMD decline with FTC/TDF remain unclear, and studies in HIV-positive individuals have been confounded by the effects of HIV and concomitant antiretroviral medications. We evaluated the impact of FTC/TDF on biomarkers of bone remodeling and bone mineral metabolism in HIV-negative men and women enrolled in the Partners PrEP Study.

Methods

In a random sample of HIV-negative participants randomized to FTC/TDF PrEP (n = 50) or placebo (n = 50), serum parathyroid hormone (PTH), bone biomarkers (C-telopeptide, procollagen 1 intact N-terminal propeptide, and sclerostin), and plasma fibroblast growth factor 23 were measured at baseline and month 24, and the percentage change was compared between groups. In a complementary analysis, we compared the change in biomarkers between participants with and without a 25% decline in glomerular filtration rate (GFR) on FTC/TDF.

Results

Baseline characteristics were similar between the groups (median age, 38 years; 40% women). Vitamin D insufficiency was common, but baseline GFR and PTH were in the normal range. We observed a significantly greater percent increase in serum C-telopeptide in participants randomized to FTC/TDF vs placebo (P = .03), suggesting an increase in bone remodeling. We observed no differences in the other biomarkers, or in a separate analysis comparing participants with and without a decline in GFR.

Conclusions

Increased bone remodeling may mediate the BMD decline observed with tenofovir-containing PrEP and antiretroviral therapy, independent of a TDF-mediated decrease in kidney function.
Clinical Impact of Revised Cefepime Breakpoint in Patients With Enterobacteriaceae Bacteremia
Authors: Foong Kap Sum , Carlson Abigail L , Munigala Satish , Burnham Carey-Ann D , Warren David K
Published: August 2019

The impact of the revised Clinical and Laboratory Standards Institute interpretative criteria for cefepime in Enterobacteriaceae remains unclear. We applied the new breakpoint on 644 previously defined cefepime-susceptible Enterobacteriaceae isolates. We found no differences in mortality or microbiological failure, regardless of isolates being susceptible or cefepime-susceptible dose-dependent by current criteria.
Eight-Year-Old Male With Primary Amebic Meningoencephalitis
Authors: Vareechon Chairut , Tarro Thomas , Polanco Claudia , Anand Vikram , Pannaraj Pia S , Dien Bard Jennifer
Published: August 2019

Naegleria fowleri is a thermophilic free-living amoeba that is found in warm, fresh water and causes primary amebic meningoencephalitis (PAM). The following report demonstrates the rapid and destructive clinical features of PAM in an 8-year-old male who presented with severe headaches approximately 12 days after swimming in a hot spring.
Contrast Dispersion on Epidurography May Be Associated with Clinical Outcomes After Percutaneous Epidural Neuroplasty Using an Inflatable Balloon Catheter
Authors: Kim Doo-Hwan , Ji Gyu Yeul , Kwon Hyun-Jung , Na Taejun , Shin Jin-Woo , Shin Dong Ah , Choi Seong-Soo
Published: August 2019

Background

Contrast dispersion pattern on epidurography may be associated with clinical improvement after epidural neuroplasty. However, insufficient evidence supports this theory. The current study aims to evaluate the relevance of contrast dispersion and clinical improvement after percutaneous epidural neuroplasty using an inflatable balloon catheter.

Methods

One hundred patients with lumbar spinal stenosis who underwent combined balloon decompression and epidural adhesiolysis between March 2015 to December 2015 participated in the present study. Participants were divided into two groups by contrast dispersion pattern on postprocedural epidurography: the complete contrast dispersion (CCD) and incomplete contrast dispersion (ICCD) groups. The numeric rating scale (NRS), Oswestry Disability Index (ODI), and global perceived effects (GPE) were each assessed before and one, three, six, nine, and 12 months after the intervention.

Results

After combined balloon decompression and adhesiolysis, significant pain reduction and functional improvement were maintained up to 12 months in patients with lumbar spinal stenosis. NRS and GPE in the CCD group were significantly lower than in the ICCD group from six to 12 months after the intervention. The ODI in the CCD group was also significantly lower compared with that in the ICCD group from one to 12 months after the intervention.

Conclusions

Combined balloon decompression and adhesiolysis with the inflatable balloon catheter can provide noteworthy pain reduction and improvement of physical function for a long-term period in patients with lumbar spinal stenosis. Because CCD showed better clinical improvement compared with ICCD, a contrast dispersion pattern may be associated with an improved clinical outcome.
Practice Patterns in Perioperative Nonopioid Analgesic Administration by Anesthesiologists in a Veterans Affairs Hospital
Authors: Kwong Jereen Z , Mudumbai Seshadri C , Hernandez-Boussard Tina , Popat Rita A , Mariano Edward R
Published: August 2019

Objective

Although multimodal analgesia (MMA) is recommended for perioperative pain management, previous studies have found substantial variability in its utilization. To better understand the factors that influence anesthesiologists’ choices, we assessed the associations between patient or surgical characteristics and number of nonopioid analgesic modes received intraoperatively across a variety of surgeries in a university-affiliated Veteran Affairs hospital.

Methods

We included elective inpatient surgeries (orthopedic, thoracic, spine, abdominal, and pelvic procedures) that used at least one nonopioid analgesic within a one-year period. Multivariable multinomial logistic regression models were used to estimate adjusted odds ratios and 95% confidence intervals (CIs). We also described the combinations of analgesia used in each surgical subtype and conducted exploratory analyses to test the associations between the number of modes used and postoperative outcomes.

Results

Of the 1,087 procedures identified, 33%, 53%, and 14% were managed with one, two, and three or more modes, respectively. Older patients had lower odds of receiving three or more modes (adjusted odds ratio [aOR] = 0.28, 95% confidence interval [CI] = 0.15–0.52), as were patients with more comorbidities (two modes: aOR = 0.87, 95% CI = 0.79–0.96; three or more modes: aOR = 0.81, 95% CI = 0.71–0.94). Utilization varied across surgical subtypes P < 0.0001). Increasing the number of modes, particularly use of regional anesthesia, was associated with shorter length of stay.

Conclusions

Our study suggests that age, comorbidities, and surgical type contribute to variability in MMA utilization. Risks and benefits of multiple modes should be carefully considered for older and sicker patients. Future directions include developing patient- and procedure-specific perioperative MMA recommendations.
Research Synthesis
Authors: Roberts Caroline , Gilbert Emily , Allum Nick , Eisner Léïla
Published: August 2019

Herbert Simon’s (1956) concept of satisficing provides an intuitive explanation for the reasons why respondents to surveys sometimes adopt response strategies that can lead to a reduction in data quality. As such, the concept rapidly gained popularity among researchers after it was first introduced to the field of survey methodology by Krosnick and Alwin (1987), and it has become a widely cited buzzword linked to different forms of response error. In this article, we present the findings of a systematic review involving a content analysis of journal articles published in English-language journals between 1987 and 2015 that have drawn on the satisficing concept to evaluate survey data quality. Based on extensive searches of online databases, and an initial screening exercise to apply the study’s inclusion criteria, 141 relevant articles were identified. Guided by the theory of survey satisficing described by Krosnick (1991), the methodological features of the shortlisted articles were coded, including the indicators of satisficing analyzed, the main predictors of satisficing, and the presence of main or interaction effects on the prevalence of satisficing involving indicators of task difficulty, respondent ability, and respondent motivation. Our analysis sheds light on potential differences in the extent to which satisficing theory holds for different types of response error, and highlights a number of avenues for future research.
Angiotensin-converting enzyme 2 attenuates inflammatory response and oxidative stress in hyperoxic lung injury by regulating NF-κB and Nrf2 pathways
Authors: Fang Y , Gao F , Liu Z
Published: August 2019

Objective

To investigate the role of angiotensin-converting enzyme 2 (ACE2) in hyperoxic lung injury.

Methods

Adult mice were exposed to 95% O2 for 72 h to induce hyperoxic lung injury, and simultaneously treated with ACE2 agonist diminazene aceturate (DIZE) or inhibitor MLN-4760. ACE2 expression/activity in lung tissue and angiotensin (Ang)-(1–7)/Ang II in bronchoalveolar lavage fluid (BALF), and the severity of hyperoxic lung injury were evaluated. The levels of inflammatory factors in BALF and lung tissue and the expression levels of phospho-p65, p65 and IkBα were measured. Oxidative parameter and antioxidant enzyme levels in lung tissue were measured to assess oxidative stress. Finally, the expression levels of nuclear factor-erythroid-2-related factor (Nrf2), NAD(P)H quinine oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were measured using Western blotting.

Results

Hyperoxia treatment significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1–7) ratio, while co-treatment with hyperoxia and DIZE significantly increased lung ACE2 expression/activity and decreased the Ang II/Ang-(1–7) ratio. By contrast, co-treatment with hyperoxia and MLN-4760 significantly decreased lung ACE2 expression/activity and increased the Ang II/Ang-(1–7) ratio. Hyperoxia treatment induced significant lung injury, inflammatory response and oxidative stress, which were attenuated by DIZE but aggravated by MLN-4760. The NF-κB pathways were activated by hyperoxia and MLN-4760 but inhibited by DIZE. The Nrf2 pathway and its downstream proteins NQO1 and HO-1 were activated by DIZE but inhibited by MLN-4760.

Conclusion

Activation of ACE2 can reduce the severity of hyperoxic lung injury by inhibiting inflammatory response and oxidative stress. ACE2 can inhibit the NF-κB pathway and activate the Nrf2/HO-1/NQO1 pathway, which may be involved in the underlying mechanism.
Tuberculosis in people with rheumatic disease in Finland 1995–2007: a nationwide retrospective register study
Authors: Vuorela Marjo , Mars Nina J , Salonen Juha , Kauppi Markku J
Published: August 2019

Objectives

RA and its medication, especially TNF-α inhibitors, increase the risk of clinical tuberculosis (TB) infection. We aimed to investigate the clinical manifestations, incidence and temporal changes in TB occurring concurrently with rheumatic diseases (RDs) between 1995 and 2007.

Methods

We combined the register of the Social Insurance Institution of Finland and the National Infectious Disease Register to find adult patients with reimbursed DMARDs and with a TB notification between 1995 and 2007. After reviewing the medical records, we described their clinical manifestations and medications, explored TB incidence trends using Poisson regression, and compared the incidence of TB with that of the general population.

Results

We identified 291 patients with both TB and rheumatic disease (RD), 196 of whom had RA. Between 1995 and 2007, the incidence of TB in adult RD decreased from 58.8 to 30.0 per 100 000 (trend P < 0.001, average marginal effect −3.4/100 000 per year, 95% CI −4.4, −2.4). Compared with the general population, the incidence was ∼4-fold. Among RD patients, pulmonary TB was the most common form of TB (72.6%). Disseminated TB was present in 56 (19.6%) patients.

Conclusion

The incidence of TB among RD patients was ∼4-fold that of the general population, and it declined between 1995 and 2007. Disseminated TB was present in nearly 20% of patients.
Haematological abnormalities in new-onset rheumatoid arthritis and risk of common infections: a population-based study
Authors: Nikiphorou Elena , de Lusignan Simon , Mallen Christian , Khavandi Kaivan , Roberts Jacqueline , Buckley Christopher D , Galloway James , Raza Karim
Published: August 2019

Objectives

To describe the prevalence of haematological abnormalities in individuals with RA at the point of diagnosis in primary care and the associations between haematological abnormalities, vaccinations and subsequent risk of common infections.

Methods

We studied 6591 individuals with newly diagnosed RA between 2004 and 2016 inclusive using the UK Royal College of General Practitioners Research and Surveillance Centre primary care database. The prevalence of haematological abnormalities at diagnosis (anaemia, neutropenia and lymphopenia) was established. Cox proportional hazards models were used to evaluate the association between each haematological abnormality and time to common infections and the influence of vaccination status (influenza and pneumococcal vaccine) on time to common infections in individuals with RA compared with a matched cohort of individuals without RA.

Results

Anaemia was common at RA diagnosis (16.1% of individuals), with neutropenia (0.6%) and lymphopenia (1.4%) less so. Lymphopenia and anaemia were associated with increased infection risk [hazard ratio (HR) 1.18 (95% CI 1.08, 1.29) and HR 1.37 (95% CI 1.08, 1.73), respectively]. There was no evidence of an association between neutropenia and infection risk [HR 0.94 (95% CI 0.60, 1.47)]. Pneumonia was much more common in individuals with early RA compared with controls. Influenza vaccination was associated with reduced risk of influenza-like illness only for individuals with RA [HR 0.58 (95% CI 0.37, 0.90)].

Conclusion

At diagnosis, anaemia and lymphopenia, but not neutropenia, increase the risk of common infections in individuals with RA. Our data support the effectiveness of the influenza vaccination in individuals with RA.
Competence-based learning in engineering mechanics in an adaptive online learning environment
Authors: Linke Markus , Landenfeld Karin
Published: August 2019

In engineering sciences like mechanical or automotive engineering, pre-knowledge in mathematics is required to follow deeply specific engineering lectures. Mathematical skills are essential preconditions to successfully complete engineering lectures. It is necessary that these preconditions are identified for each individual student so that suitable learning opportunities can be provided according to the individual student needs. Within this paper an approach of competence-based learning in engineering mechanics is presented. This approach is assisted by an online learning environment that is adapted and extended by several features in order to enable a competence-oriented learning strategy. Computer-assisted tests are used for measuring mathematical pre-knowledge and pre-skills. Moreover, a mastery learning approach based on exercises is utilized in order to secure a certain skill level before students move forward to learn subsequent competencies. Test results influence the individual learning path by offering different learning elements to each student.
Polybrominated Diphenylether (DE-71) Exposure Skews Phenotypic Sex Ratio, and Alters Steroid Hormone Levels and Steroidogenic Enzyme Activities in Juvenile Silurana tropicalis
Authors: Fort Douglas J , Mathis Michael , Fort Chelsea , Fort Troy D , Guiney Patrick D , Weeks John A
Published: August 2019

The impact of the brominated flame-retardant mixture, DE-71, on gonadal steroidogenesis during sexual differentiation in Silurana tropicalis was examined. A partial lifecycle study exposing S. tropicalis to varying concentrations of DE-71 (0.0, 0.65, 1.3, 2.5, and 5.0 μg/l [nominal]) was conducted from early gastrula-stage embryo to 150 days postmetamorphosis (dpm). Exposure of S. tropicalis to DE-71 induced liver necrosis and induced abnormal ovary development characterized by previtellogenic oocyte necrosis and arrested development of vitellogenic oocytes in females in a concentration-dependent manner. Decreased mean plasma dihydrotestosterone (DHT) and T, gonad T, and increased mean plasma E2 levels were found in 150 dpm DE-71-treated male S. tropicalis compared to controls. Plasma E2 levels in females were not significantly altered compared to control S. tropicalis, although lower plasma and gonad T were detected. Mean gonadal CYP 19 aromatase activity in both male and female S. tropicalis exposed to DE-71 was not appreciably affected. Decreased mean male 5α-reductase and CYP17 activities in both male and females were observed compared to control frogs. Overall, these studies suggested that PBDE exposure induced liver necrosis and abnormal ovary development; and reduced circulating and gonadal androgens resulting in a phenotypic skew in sex ratio toward the female sex in S. tropicalis.
Phylogenetic analysis and revision of the strangest lace bug subfamily Vianaidinae (Heteroptera: Tingidae)
Authors: Guidoti Marcus , Montemayor Sara Itzel , Campos Luiz Alexandre , Guilbert Eric
Published: August 2019

In this study, we present a taxonomic review of a rarely collected subfamily of lace bugs (Vianaidinae: Tingidae: Heteroptera), including the description of nine new species and one new genus, and a phylogenetic analysis targeting its internal relationships. Anommatocoris araguanus sp. nov., A. knudsoni sp. nov., A. schuhi sp. nov., A. serratus sp. nov., A. sucreanus sp. nov., Thaumamannia insolita sp. nov. and T. urucuana sp. nov. are proposed, in addition to the new genus Henryvianaida gen. nov. with its two macropterous species, H. colombiensis sp. nov. and H. machupicchuensis sp. nov. The monophyly of all vianaidine genera is recovered and their synapomorphies are highlighted. Comments on fossil forms and insights on the future of Vianaidinae taxonomy and systematics are also included.
Hygienic personalities in wild grey mouse lemurs vary adaptively with sex
Authors: Poirotte Clémence , Kappeler Peter M.
Published: August 2019

Detecting the risk of infection and minimizing parasite exposure represent the first lines of host defence against parasites. Individuals differ in the expression of these behavioural defences, but causes of such variation have received little empirical attention. We therefore experimentally investigated the effects of several individual and environmental factors on the expression level of faecal avoidance in the context of feeding, drinking, sleeping and defecating in a wild primate population. We found a strong sex bias in the expression level of anti-parasite behaviours of grey mouse lemurs (Microcebus murinus), with only females strongly avoiding contaminated food, water and nests, and exhibiting selective defecation. Our results further suggest that individuals adapted their protective behaviours according to variation in intrinsic and ecological factors that may influence the cost–benefit balance of behavioural defences. Overall, individuals exhibited high consistency of investment in protective behaviours across behavioural contexts and time, suggesting that grey mouse lemurs exhibit different hygienic personalities. Finally, the global hygienic score was negatively correlated with faecal–orally transmitted parasite richness, suggesting that variation in behavioural defence has fitness consequences. We suggest that integrating inter-individual variation in behavioural defences in epidemiological studies should improve our ability to model disease spread within populations.
Azteca
ants maintain unique microbiomes across functionally distinct nest chambers
Authors: Lucas Jane M. , Madden Anne A. , Penick Clint A. , Epps Mary Jane , Marting Peter R. , Stevens Julia L. , Fergus Daniel J. , Dunn Robert R. , Meineke Emily K.
Published: August 2019

The microbiome of built structures has considerable influence over an inhabitant's well-being, yet the vast majority of research has focused on human-built structures. Ants are well-known architects, capable of constructing elaborate dwellings, the microbiome of which is underexplored. Here, we explore the bacterial and fungal microbiomes in functionally distinct chambers within and outside the nests of
Azteca alfari
ants in
Cecropia peltata
trees. We predicted that
A. alfari
colonies (1) maintain distinct microbiomes within their nests compared to the surrounding environment, (2) maintain distinct microbiomes among nest chambers used for different functions, and (3) limit both ant and plant pathogens inside their nests. In support of these predictions, we found that internal and external nest sampling locations had distinct microbial communities, and
A. alfari
maintained lower bacterial richness in their ‘nurseries’. While putative animal pathogens were suppressed in chambers that ants actively inhabited, putative plant pathogens were not, which does not support our hypothesis that
A. alfari
defends its host trees against microbial antagonists. Our results show that ants influence microbial communities inside their nests similar to studies of human homes. Unlike humans, ants limit the bacteria in their nurseries and potentially prevent the build-up of insect-infecting pathogens. These results highlight the importance of documenting how indoor microbiomes differ among species, which might improve our understanding of how to promote indoor health in human dwellings.
Skewed temperature dependence affects range and abundance in a warming world
Authors: Hurford Amy , Cobbold Christina A. , Molnár Péter K.
Published: August 2019

Population growth metrics such asR0are usually asymmetric functions of temperature, with cold-skewed curves arising when the positive effects of a temperature increase outweigh the negative effects, and warm-skewed curves arising in the opposite case. Classically, cold-skewed curves are interpreted as more beneficial to a species under climate warming, because cold-skewness implies increased population growth over a larger proportion of the species's fundamental thermal niche than warm-skewness. However, inference based on the shape of the fitness curve alone, and without considering the synergistic effects of net reproduction, density and dispersal, may yield an incomplete understanding of climate change impacts. We formulate a moving-habitat integrodifference equation model to evaluate how fitness curve skewness affects species’ range size and abundance during climate warming. In contrast to classic interpretations, we find that climate warming adversely affects populations with cold-skewed fitness curves, positively affects populations with warm-skewed curves and has relatively little or mixed effects on populations with symmetric curves. Our results highlight the synergistic effects of fitness curve skewness, spatially heterogeneous densities and dispersal in climate change impact analyses, and that the common approach of mapping changes only inR0may be misleading.
Investigating the attitudes of Canadian paramedic students towards homelessness
Authors: Cochrane Alyson , Pithia Priya , Laird Emma , Mifflin Kelly , Sonley-Long Venessa , Batt Alan M.
Published: August 2019

Introduction

When paramedics are dispatched, it is expected that every patient receives the same level of care regardless of variable factors. Homelessness is a growing social issue across Canada that is particularly prevalent in urban areas. The quality of healthcare delivered to individuals experiencing homelessness may be influenced by negative attitudes held by healthcare professionals. There is an absence of literature quantifying the perspectives of paramedics towards homelessness; therefore, the focus of this study was to identify the attitudes of paramedic students towards homelessness and to continue the conversation in regards to the evolving educational needs of paramedic students.

Methods

This study employed a longitudinal design of a convenience sample of first year paramedic students in a college program in Ontario, Canada. The ‘Health Professional’s Attitude Towards the Homeless Inventory’ (HPATHI) was distributed to participants before and after placement and clinical exposure. The questionnaire includes 19 statements which participants respond to on a Likert scale. Mean scores were calculated, and statements were categorized into attitudes, interest, and confidence. Data were collected post-placement on interactions with persons experiencing homelessness.

Results

A total of 52 first year paramedic students completed the HPATHI pre-placement and 47 completed the questionnaire post-placement. Mean scores for attitudes (pre 3.64, SD 0.49; post 3.85, SD 0.38, p=0.032), interest (pre 3.91, SD 0.40; post 3.84, SD 0.39,p=0.51) and confidence (pre 4.02, SD 0.50; post 3.71, SD 0.67, p=0.004) were largely positive, but there was a demonstrated decreasing trend in confidence with, and interest in, working with those experiencing homelessness. Participants reported an average of 60 hours of placement, during which 15 participants (32%) reported interactions with people experiencing homelessness.

Conclusion

First year paramedic students demonstrate overall positive attitudes towards those experiencing homelessness, and the mean score for attitudes improved over the surveys. However, there were demonstrable decreases in confidence and interest over time, which may be related to the type and frequency of interactions during clinical placement. Paramedic education programs may benefit from the inclusion of focused education on homelessness, specific clinical experiences, and education related to social determinants of health.
Direct Binding of Phosphatidylglycerol at Specific Sites Modulates Desensitization of a Pentameric Ligand-Gated Ion Channel
Authors: Tong Ailing , Petroff John T. , Hsu Fong-Fu , Schmidpeter Philipp A. M. , Nimigean Crina M. , Sharp Liam , Brannigan Grace , Cheng Wayland W. L.
Published: August 2019

Pentameric ligand-gated ion channels (pLGICs) are essential determinants of synaptic transmission, and are modulated by specific lipids including anionic phospholipids. The exact modulatory effect of anionic phospholipids in pLGICs and the mechanism of this effect are not well understood. Using native mass spectrometry, coarse-grained molecular dynamics simulations and functional assays, we show that the anionic phospholipid, 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), preferentially binds to and stabilizes the pLGIC, Erwinia ligand-gated ion channel (ELIC), and decreases ELIC desensitization. Mutations of five arginines located in the interfacial regions of the transmembrane domain (TMD) reduce POPG binding, and a subset of these mutations increase ELIC desensitization. In contrast, the L240A mutant known to decrease ELIC desensitization, increases POPG binding. The results support a mechanism by which POPG stabilizes the open state of ELIC relative to the desensitized state by direct binding at specific sites.
Tau Accumulation via Reduced BAG3-mediated Autophagy Is Required for GGGGCC Repeat Expansion-Induced Neurodegeneration
Authors: Wen Xue , An Ping , Li Hexuan , Zhou Zijian , Sun Yimin , Wang Jian , Ma Lixiang , Lu Boxun
Published: August 2019

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats (CAGr) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r. Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r-induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.
Early-life adversity is associated with differential gene expression in response to acute psychological stress: preliminary findings
Authors: Shalev Idan , Hastings Waylon J. , Etzel Laura , Israel Salomon , Russell Michael A. , Hendrick Kelsie A. , Zinobile Megan , Siegel Sue Rutherford
Published: August 2019

Objective

Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present study used a novel experimental design to test how young adults’ exposure to ELA influence neuroendocrine and inflammatory responses to acute stress.

Materials and methods

Participants were 12 males (mean age= 21.25), half of whom endorsed at least three significant adverse events up to age 18 years (‘ELA group’), and half who confirmed zero (‘controls’). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of NR3C1, FKBP5 and NFKB1, and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test.

Results

The ELA group evinced significantly higher cortisol response and lower NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. Cortisol and group status interacted such that increase in cortisol predicted increase in both NR3C1 and NFKB1 expression among controls, but decrease in the ELA group. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.

Conclusion

Overall, we provide preliminary findings for the biological embedding of stress via a dynamic and dysregulated pattern evidenced in response to acute psychosocial stress. ELA may program physiological systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate these findings.
Single-cell proteomics reveals downregulation of TMSB4X to drive actin release for stereocilia assembly
Authors: Zhu Ying , Scheibinger Mirko , Ellwanger Daniel C. , Krey Jocelyn F. , Choi Dongseok , Kelly Ryan T. , Heller Stefan , Barr-Gillespie Peter G.
Published: August 2019

Hearing and balance rely on small sensory hair cells that reside in the inner ear. To explore dynamic changes in the abundant proteins present in differentiating hair cells, we used nanoliter-scale shotgun mass spectrometry of single cells, each ∼1 picoliter, from utricles of embryonic day 15 chickens. We identified unique constellations of proteins or protein groups from presumptive hair cells and from progenitor cells. The single-cell proteomes enabled thede novoreconstruction of a developmental trajectory. Inference of protein expression dynamics revealed that the actin monomer binding protein thymosin β4 (TMSB4X) was present in progenitors but dropped precipitously during hair-cell differentiation. Complementary single-cell transcriptome profiling showed downregulation ofTMSB4XmRNA during maturation of hair cells. We propose that most actin is sequestered by TMSB4X in progenitor cells, but upon differentiation to hair cells, actin is released to build the sensory hair bundle.
PCR-based detection ofHelicobacterspp. in mice from different animal houses in Rio de Janeiro, Brazil
Authors: Matos-Rodrigues Gabriel E. , Masseron Carolinne C. , da Silva Fabio J. Moreira , Flajblat Marcel , Moreira Lilian O. , Martins Rodrigo A. P.
Published: August 2019

Pathogenic microbial detection and control in breeding and experimental laboratory animal facilities is essential to guarantee animal welfare, data validity and reproducibility.Helicobacter spp.is known to severely affect mice health, mainly in immunocompromised strains, what may affect experimental outcomes. This study aimed to screen forHelicobacter spp.in mice from four different animal houses in Rio de Janeiro, Brazil using a PCR for 16S ribosomal RNA. A pair of primers was designed to specifically identifyHelicobacterspecies that commonly infect laboratory mice. Following PCR reaction, the expected 375 base pairs (bp) amplification product was purified, sequenced and showed a 95% similarity when compared to deposited sequences ofHelicobacter hepaticusandHelicobacter bilis. Then, the presence ofHelicobacter spp.in both feces and intestines samples was analyzed.Helicobacter sppDNA was detected in 59.6% of the fecal and 70.17% of the intestine samples. AlthoughHelicobacter sppscreening is recommended by institutional animal health monitoring programs worldwide it is still not mandatory by Brazilian animal welfare regulation. Our study, the first to monitorHelicobacterspecies in laboratory mice in Brazil, demonstrates the possibility of using a low cost, rapid molecular diagnostic test to screenHelicobacterand highlights the importance of regular microbiological verification of mice used for research in Brazilian animal houses.
Mechanisms of Chromosomal Instability in High-grade Serous Ovarian Carcinoma
Authors: Tamura N. , Shaikh N. , Muliaditan D. , McGuinness J. , Moralli D. , Durin M. A. , Green C. M. , Bowtell D. , Balkwill F. R. , Curtius K. , McClelland S. E.
Published: August 2019

Chromosomal instability (CIN), the continual gain and loss of chromosomes or parts of chromosomes, occurs in the majority of cancers and confers poor prognosis. Mechanisms driving CIN remain unknown in most cancer types due to a scarcity of functional studies. High-grade serous ovarian carcinoma (HGSC), the most common subtype of ovarian cancer, is the major cause of death due to gynaecological malignancy in the Western world with chemotherapy resistance developing in almost all patients. HGSC exhibits high rates of chromosome aberrations and knowledge of causative mechanisms is likely to represent an important step towards combating the poor prognosis of this disease. However, very little is known about the nature of chromosomal instability exhibited by this cancer type in particular due to a historical lack of appropriate cell line models. Here we perform the first in-depth functional characterisation of mechanisms driving CIN in HGSC by analysing eight cell lines that accurately recapitulate HGSC genetics as defined by recent studies. We show, using a range of established functional CIN assays combined with live cell imaging and single molecule DNA fibre analysis, that multiple mechanisms co-exist to drive CIN in HGSC. These include supernumerary centrosomes, elevated microtubule dynamics and DNA replication stress. By contrast, the spindle assembly checkpoint was intact. These findings are relevant for developing therapeutic approaches to manipulating CIN in ovarian cancer, and suggests that such approaches may need to be multimodal to combat multiple co-existing CIN drivers.
Heating quinoa shoots results in yield loss by inhibiting fruit production and delaying maturity
Authors: Tovar Jose C. , Quillatupa Carlos , Callen Steven T. , Castillo S. Elizabeth , Pearson Paige , Shamin Anastasia , Schuhl Haley , Fahlgren Noah , Gehan Malia A.
Published: August 2019

Increasing global temperatures and a growing world population create the need to develop crop varieties that yield more in warmer climates. There is growing interest in expanding quinoa cultivation, because of quinoa’s ability to produce nutritious grain in poor soils, with little water and at high salinity. However, the main limitation to expanding quinoa cultivation is quinoa’s susceptibility to temperatures above ~32°C. This study investigates the phenotypes, genes, and mechanisms that may affect quinoa seed yield at high temperatures. By using a differential heating system where only roots or only shoots were heated, quinoa yield losses were attributed to shoot heating. Plants with heated shoots lost 60% to 85% yield as compared to control. Yield losses were due to lower fruit production, which lowered the number of seeds produced per plant. Further, plants with heated shoots had delayed maturity and more non-reproductive shoot biomass, while plants with both heated roots and heated shoots produced more yield from panicles that escaped heat than control. This suggests that quinoa uses a type of avoidance strategy to survive heat. Gene expression analysis identified transcription factors differentially expressed in plants with heated shoots and low yield that had been previously associated with flower development and flower opening. Interestingly, in plants with heated shoots, flowers stayed closed during the day while control flowers were open. Although a closed flower may protect floral structures, this could also cause yield losses by limiting pollen dispersal, which is necessary to produce fruit in quinoa’s mostly female flowers.

Significance Statement

This study provides evidence that heating quinoa during flowering results in seed yield loss by lowering fruit production. Plants with low yield after heat treatment also matured more slowly, suggesting that quinoa may use a type of avoidance strategy to survive heat stress conditions. Genes differentially expressed under heat include genes involved in flower development and flower opening.
Cognitive ability, Socioeconomic Status, and Depressive Symptoms: A Gene-Environment-Trait Correlation
Authors: Avinun Reut
Published: August 2019

Purpose

Depression is genetically influenced, but the mechanisms that underlie these influences are largely unknown. Recently, shared genetic influences were found between depression and both cognitive ability and educational attainment (EA). Although genetic influences are often thought to represent direct biological pathways, they can also reflect indirect pathways, including modifiable environmental mediations (gene-environment-trait correlations). Here, I tested whether the genetic correlation between cognitive ability and depressive symptoms partly reflects an environmental mediation involving socioeconomic status (SES).

Methods

As previously done to increase statistical power, and due to their high phenotypic and genetic correlation, EA was used as a proxy for cognitive ability. Summary statistics from a recent genome-wide association study of EA were used to calculate EA polygenic scores. Two independent samples were used: 522 non-Hispanic Caucasian university students from the Duke Neurogenetics Study (277 women, mean age 19.78±1.24 years) and 5,243 white British volunteers (2,669 women, mean age 62.30±7.41 years) from the UK biobank.

Results

Mediation analyses in the two samples indicated that higher proxy-cognitive ability polygenic scores predicted higher SES, which in turn predicted lower depressive symptoms.

Conclusion

Current findings suggest that some of the genetic correlates of depressive symptoms depend on an environmental mediation and consequently that modifying the environment, specifically through social and economic policies, can affect the genetic influences on depression. Additionally, these results suggest that findings from genetic association studies of depression may be context-contingent and reflect social, cultural, and economic processes in the examined population.
NeuroGPU: Accelerating multi-compartment, biophysically detailed neuron simulations on GPUs
Authors: Ben-Shalom Roy , Artherya Nikhil S. , Ladd Alexander , Cross Christopher , Sanghevi Hersh , Kim Kyung Geun , Korngreen Alon , Bouchard Kristofer E. , Bender Kevin J.
Published: August 2019

The membrane potential of individual neurons depends on a large number of interacting biophysical processes operating on spatial-temporal scales spanning several orders of magnitude. The multi-scale nature of these processes dictates that accurate prediction of membrane potentials in specific neurons requires utilization of detailed simulations. Unfortunately, constraining parameters within biologically detailed neuron models can be difficult, leading to poor model fits. This obstacle can be overcome partially by numerical optimization or detailed exploration of parameter space. However, these processes, which currently rely on central processing unit (CPU) computation, often incur exponential increases in computing time for marginal improvements in model behavior. As a result, model quality is often compromised to accommodate compute resources. Here, we present a simulation environment, NeuroGPU, that takes advantage of the inherent parallelized structure of graphics processing unit (GPU) to accelerate neuronal simulation. NeuroGPU can simulate most of biologically detailed models 800x faster than traditional simulators when using multiple GPU cores, and even 10-200 times faster when implemented on relatively inexpensive GPU systems. We demonstrate the power of NeuoGPU through large-scale parameter exploration to reveal the response landscape of a neuron. Finally, we accelerate numerical optimization of biophysically detailed neuron models to achieve highly accurate fitting of models to simulation and experimental data. Thus, NeuroGPU enables the rapid simulation of multi-compartment, biophysically detailed neuron models on commonly used computing systems accessible by many scientists.
The geographic distribution of reef and oceanic manta rays in the south-east Indian and south-west Pacific Oceans
Authors: Armstrong Amelia J. , Armstrong Asia O. , Bennett Michael B. , McGregor Frazer , Abrantes Kátya G. , Barnett Adam , Richardson Anthony J. , Townsend Kathy A. , Dudgeon Christine L
Published: August 2019

The reef manta ray,Mobula alfredi, occurs in tropical and warm temperate coastal waters, and around islands and reefs in the Pacific and Indian Oceans. Published records that relate to the distribution ofM. alfrediin the south-east Indian and south-west Pacific Oceans are largely restricted to locations where there is a focus on manta ray ecotourism, with little information from elsewhere. Even less is known about the circumglobally distributed oceanic manta ray,Mobula birostris, for which there are few published sighting records. We collatedn =11,703 sighting records from Australian waters and offshore territories forM. alfredisourced from scientific image databases (n= 10,715), aerial surveys (n= 375) and online reports (n= 613). From collated records, we confirm that the species shows an uninterrupted distribution within Australian coastal waters north of 26°S on the west coast to 31°S on the east coast, with a southernmost record at 34°S. Confirmed locations forM. birostrisencompass a latitudinal range of 10-40°S. Records from more southerly locations relate to warm-water events. Sightings ofM. birostriswere rare, but were confirmed at several geographically separate locations, probably reflecting its preference for offshore waters. The study clarifies the occurrence and range of each species within coastal waters of the south-east Indian and south-west Pacific Oceans, and highlights regions in northern Australia that are of specific interest for future research into possible movements of individuals between international marine jurisdictions.
Evolution of conserved noncoding sequences in Arabidopsis thaliana
Authors: Yocca Alan E. , Lu Zefu , Schmitz Robert J. , Freeling Michael , Edger Patrick P.
Published: August 2019

Recent pangenome studies have revealed a large fraction of the gene content within a species exhibits presence-absence variation (PAV). However, coding regions alone provide an incomplete assessment of functional genomic sequence variation at the species level. Little to no attention has been paid to noncoding regulatory regions in pangenome studies, though these sequences directly modulate gene expression and phenotype. To uncover regulatory genetic variation, we generated chromosome-scale genome assemblies for thirty Arabidopsis thaliana accessions from multiple distinct habitats and characterized species level variation in Conserved Noncoding Sequences (CNS). Our analyses uncovered not only evidence for PAV and positional variation (PosV) but that diversity in CNS is non-random, with variants shared across different accessions. Using evolutionary analyses and chromatin accessibility data, we provide further evidence supporting roles for conserved and variable CNS in gene regulation. Characterizing species-level diversity in all functional genomic sequences may later uncover previously unknown mechanistic links between genotype and phenotype.
Genotype-by-environment interactions for seminal fluid expression and sperm competitive ability
Authors: Patlar Bahar , Ramm Steven A.
Published: August 2019

Sperm competition commonly occurs whenever females mate multiply, leading to variation in male paternity success. This can be due to variation in the various traits that might affect sperm competitive ability, which itself depends on both genetic and environmental factors, as well as on genotype-by-environment interactions (GEI). Seminal fluid is a major component of the male ejaculate that is often expected to mediate sperm competition, where different genotypes can differ in their seminal fluid expression as a response to different level of sperm competition (i.e., exhibit GEI). We therefore here focussed on testing for GEI in expression of two recently identified seminal fluid transcripts,suckless-1andsuckless-2, which potentially modulate sperm competitive ability in the simultaneously hermaphroditic flatwormMacrostomum lignanovia their effects on manipulating post-mating partner behaviour and ultimately the fate of transferred ejaculates. In addition, we sought to test for GEI in sperm competitive ability, to investigate the relationship between natural variation in the expression of these seminal fluid transcripts generated through GEI and relative paternity success. To do so, we manipulated social group size, which has been shown to successfully alter sperm competition level inM. lignano, in a set of inbred lines (genotypes) and then measured both the expression level ofsuckless-1andsuckless-2in focal worms together with their relative paternity success in a standardised sperm competition (P1&P2) assay. We found GEI for the expression level ofsuckless-1andsuckless-2, as well as for sperm competitive ability. Moreover, we found a positive relation between the expression ofsuckless-1and paternity success. This suggests that natural variation in the expression of this seminal fluid transcript indeed can influence sperm competition outcomes inM. lignano.