bluuebunny/crossref_metadata_2025 huggingface dataset:
Treating Posttraumatic Stress Disorder in the Presence of Acute Suicide Risk in Veterans and Active Duty Service Members
Authors: Holliday Ryan , Holder Nicholas , Olson-Madden Jennifer H. , Monteith Lindsey L.
Published: June 2019

Posttraumatic stress disorder (PTSD) is associated with increased risk for suicide, and clinicians often encounter acute suicide risk during the process of intervening upon PTSD. Although the Department of Veterans Affairs (VA) and the Department of Defense (DoD) have disseminated evidence-based treatments for PTSD, prior clinical trials have used inconsistent definitions and unclear assessment methods of suicide risk. Consequently, translating findings from PTSD treatment research to clinical practice remains challenging. This article describes challenges inherent to the current PTSD interventional research literature related to concurrent acute suicide risk among veterans and active duty service members. We reviewed prior trials and how their assessment methods and nomenclature compare with strategies and definitions mandated within the VA/DoD. Furthermore, we describe methodological recommendations for future research, including consistent use of mandated universal suicide nomenclature, standardization for classifying suicide risk, transparency in reporting assessment means and measures, and examination of current models of PTSD treatment in the context of acute suicide risk.
Truncal blocks and teenager postoperative pain perception after laparoscopic surgical procedures
Authors: Visoiu Mihaela , Chelly Jacques , Kenkre Tanya
Published: June 2019

Introduction:

The prevalence of moderate to severe pain is high in hospitalized teenage patients admitted to surgical services.

Objectives:

The aims of this study were to determine (1) the preoperative and postoperative factors influencing teenager postoperative pain perception; and (2) suffering, defined as the patient's anxiety, pain catastrophizing thoughts, and mood.

Methods:

Data were collected from medical records and from 2 medical interviews at the time of enrollment and postoperative day 1. Stepwise linear regression was conducted to assess variables that predicted teenagers' pain scores and suffering.

Results:

Two hundred two patients (mean age = 13.8 years, SD = 1.9), 56.4% females, scheduled for laparoscopic surgical procedures completed the study. The variables found to be significant predictors of pain response in teenagers were pain on the day of surgery (6.81, 95% confidence interval [CI] = 0.08–13.55, P = 0.05) and use of regional anesthesia (single-injection rectus sheath, transversus abdominis plane, and paravertebral nerve blocks) (−6.58, 95% CI = −12.87 to −0.30, P = 0.04). The use of regional anesthesia was found to predict mood responses (all patients: 2.60, 95% CI = 0.68–4.52, P = 0.01; girls: 3.45, 95% CI = 0.96–5.93, P = 0.01; 14–17-year-old teens: 2.77, 95% CI = 0.44–5.10, P = 0.02) and to negatively predict catastrophic thoughts among all patients as a group (−4.35, 95% CI = −7.51 to −1.19, P = 0.01) and among 14- to 17-year-old teens (−5.17, 95% CI = −9.44 to −0.90, P = 0.02).

Conclusion:

A comprehensive pain approach that includes truncal blocks may improve teenagers' postoperative pain control after laparoscopic surgeries.
Removal of Nasal Silicone Implant and the Impact of Subsequent Capsulectomy
Authors: Kook Won S. , Yang Chae E. , Lew Dae H.
Published: June 2019

Background:

Little is known about contributory factors of unremoved periimplant capsule causing nasal deformities after postrhinoplasty silicone implant extraction. This study investigated the impact of retained capsule causing contracture deformity and effect of subsequent capsulectomy in preventing and correcting the deformity.

Methods:

A total of 103 patients underwent secondary surgery for silicone implant removal and grafted cartilage between May of 2015 and June of 2017. Among them, 67 patients without septal extension graft or open wound and with 8-week or more follow-up were analyzed retrospectively. All operations were approached with an intranasal incision. Three procedures were performed: (1) removal of implant plus tip graft only (n = 12), (2) removal of implant plus tip graft plus subtotal capsulectomy (n = 47), and (3) removal of implant plus tip graft plus subtotal capsulectomy in patients with contraction and thick capsule (n = 8). Preremoval/postremoval of nasal bridge length index and nasolabial angle were measured with the lateral view.

Results:

In group 1, nasal bridge length index decreased by 6.2 percent and nasolabial angle increased by 5.7 percent. In group 2, nasal bridge length index increased by 2.5 percent and nasolabial angle decreased by 2.2 percent. In group 3, nasal bridge length index increased by 8.6 percent and nasolabial angle decreased by 7.9 percent.

Conclusions:

For patients undergoing surgical removal of a nasal silicone implant with or without cartilage, a concomitant capsulectomy is required to prevent potential contractures and to minimize tip deformity. Capsulectomy can release and lengthen the contracted nose without septal extension or derotation grafting. Dorsal skin irregularity did not occur regardless of whether capsulectomy was performed.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
High-performance acute care hospitals: Excelling across multiple emergency general surgery operations in the geriatric patient
Authors: DeWane Michael P. , Sukumar Nitin , Stolar Marilyn J. , Gill Thomas M. , Maung Adrian A. , Schuster Kevin M. , Davis Kimberly A. , Becher Robert D.
Published: June 2019

BACKGROUND

As the geriatric population grows, the need for hospitals performing high quality emergency general surgery (EGS) on older patients will increase. Identifying clusters of high-performing geriatric emergency general surgery hospitals would substantiate the need for in-depth analyses of hospital-specific structures and practices that benefit older EGS patients. The objectives of this study were therefore to identify clusters of hospitals based on mortality performance for geriatric patients undergoing common EGS operations and to determine if hospital performance was similar for all operation types.

METHODS

Hospitals in the California State Inpatient Database were included if they performed a range of eight common EGS operations in patients 65 years or older, with a minimum requirement of three of each operation performed over 2 years. Multivariable beta regression models were created to define hospital-level risk-adjusted mortality. Centroid cluster analysis was used to identify groups of hospitals based on mortality and to determine if mortality-performance differed by operation.

RESULTS

One hundred seven hospitals were included, performing a total of 24,279 operations in older patients. Hospitals separated into three distinct clusters: high, average, and low performers. The high-performing hospitals had survival rates 1 to 2 standard deviations better than the low-performers (p < 0.001). For each cluster, high performance in any one EGS operation consistently translated into high performance across all EGS operations.

CONCLUSION

Hospitals conducting EGS operations in the geriatric patient population cluster into three distinct groups based on their survival performance. High-performing hospitals significantly outperform the average and low performers across every operation. The high-performers achieve reliable, high-quality results regardless of operation type. Further qualitative research is needed to investigate the perioperative drivers of hospital performance in the geriatric EGS population.

LEVEL OF EVIDENCE

Study Type Prognostic, level III.
Food Choice Decisions of Athletes
Authors: Eck Kaitlyn M. , Byrd-Bredbenner Carol
Published: June 2019

Unique pressures placed on athletes make them vulnerable to disordered eating behaviors. Interviews were conducted with sports registered dietitian/nutritionists' (RDNs) (n = 15) to explore factors influencing athletes' food choices, including RDN counseling strategies. RDNs noted that convenience, taste preference, and advice from RDNs influence athletes' food choices, which varied by sports type, with endurance athletes emphasizing carbohydrates and strength athletes emphasizing protein. RDNs highlighted the importance of individualizing advice when counseling for weight loss/gain and a multidisciplinary team approach when counseling athletes with eating disorders. Barriers faced while counseling included athletes' limited nutrition knowledge, nutrition misconceptions, and limited support from coaches.
Prophylactic Wound Drainage in Renal Transplantation: A Systematic Review
Authors: D’Souza Kenneth , Crowley Sean Patrick , Hameed Ahmer , Lam Susanna , Pleass Henry Claud , Pulitano Carlo , Laurence Jerome Martin
Published: June 2019

Background.

Adult kidney transplantation is most commonly into an extraperitoneal potential space, and surgically placed drains are used routinely in many centers. There is limited evidence of clinical benefit for prophylactic drainage in other major abdominal and vascular surgery. Transplantation is, however, a unique setting combining organ dysfunction and immunosuppression, and the risks and benefits of prophylactic drain placement are not known. This study attempts to examine existing literature to determine whether prophylactic intraoperative drains have an impact on the likelihood of perigraft fluid collections and other wound-related complications following kidney transplantation.

Methods.

A literature search of MEDLINE and EMBASE was conducted to identify published comparative studies, including recipients receiving prophylactic drains to recipients in whom drains were omitted. The main outcomes were the incidence of peritransplant fluid collections and wound-related complications. Meta-analysis was performed on these data.

Results.

Four retrospective cohort studies were deemed eligible for quantitative analysis and 1 additional conference abstract was included in qualitative discussion. A total of 1640 patients, 1023 with drains and 617 without, were included in the meta-analysis. There was a lower rate of peritransplant collections associated with the drain group (RR 0.62; 95% confidence interval, 0.42-0.90). There was no significant difference in the incidence of wound-related complications between the groups (RR 0.85; 95% confidence interval, 0.34-2.11).

Conclusions.

These data associate a higher rate of peritransplant fluid collections with omission of prophylactic drainage, without a difference in the incidence of wound-related complications. Further research is required to definitively determine the impact of drains in this patient group.
Significant Reduction of Murine Renal Ischemia-Reperfusion Cell Death Using the Immediate-Acting PrC-210 Reactive Oxygen Species Scavenger
Authors: Bath Natalie M. , Fahl William E. , Redfield Robert R.
Published: June 2019

Background.

Ischemia-reperfusion (IR) injury remains a significant problem for all solid organ transplants; thus, an important unmet need in transplantation is the prevention of IR injury. PrC-210 has demonstrated superior prevention of reactive oxygen species damage in several preclinical studies as a free radical scavenger. Here, we describe its profound efficacy in suppressing IR injury in a murine model of kidney IR injury.

Methods.

C57/B6 mice underwent laparotomy with the left renal pedicle occluded for 30 minutes to induce IR injury. Right nephrectomy was performed at the time of surgery. Mice received a single systemic dose of the PrC-210, PrC-211, or PrC-252 aminothiols 20 minutes before IR injury. Twenty-four hours following IR injury, blood and kidney tissue were collected for analysis. Kidney caspase-3 level (a marker of cell death), direct histological analysis of kidneys, and serum blood urea nitrogen (BUN) were measured in animals to assess reactive oxygen species scavenger protective efficacies.

Results.

A single systemic PrC-210 dose 20 minutes before IR injury resulted in significant reductions in (1) IR-induced kidney caspase level (P < 0.0001); caspase was reduced to levels not significantly different than control caspase levels seen in unperturbed kidneys, (2) IR-induced renal tubular injury scores (P < 0.0001); brush border loss and tubular dilation were markedly reduced, and (3) serum BUN compared with control IR injury kidneys (P < 0.0001). The ranked protective efficacies of PrC-210 > PrC-211 >> PrC-252 paralleled previous radioprotection studies of the molecules.

Conclusions.

A single PrC-210 dose, minutes before the IR insult, profoundly reduced caspase, renal tubular injury, and serum BUN in mice exposed to standard kidney IR injury. These findings support further development of the PrC-210 molecule to suppress or prevent IR injury in organ transplant and other IR injury settings.
Effect of Sodium Bicarbonate in Kidney Transplant Recipients With Chronic Metabolic Acidosis
Authors: Schulte Kevin , Püchel Jodok , Schüssel Katrin , Borzikowsky Christoph , Kunzendorf Ulrich , Feldkamp Thorsten
Published: June 2019

Background.

Metabolic acidosis (MA) is a common complication after kidney transplantation and regarded to increase mortality, graft failure, and bone fractures. Here, we conducted a retrospective cohort study to analyze the effect of sodium bicarbonate on those events.

Methods.

All kidney transplant recipients of the German health insurance Allgemeine Ortskrankenkasse (AOK) were selected, who received their transplantation between 2007 and 2015. Three groups were formed: (1) control group (no acidosis, n = 3602), (2) acidosis group (encoded acidosis, n = 370), and (3) treatment group (encoded therapy, n = 769). The study endpoints were mortality, death-censored graft failure, and bone fractures.

Results.

The prevalence of MA in the first year after transplantation was 46.2%. The 5-year patient and graft survival were 89.8% and 89.3% in the control group, 90% and 90.8% in the acidosis group, and 87.5% and 81.6% in the treatment group, respectively. The rate of bone fractures did not differ between the groups. Neither log-rank tests nor multivariable Cox regression analyses could detect a negative impact of MA on mortality (hazard ratio [HR] 0.94; confidence interval [CI] 0.67–1.30), graft failure (HR1.18; CI 0.82–1.72), or the incidence of bone fractures (HR1.19; CI 0.92–1.55). Treatment with sodium bicarbonate was associated with an increased risk of graft failure (HR1.52; CI 1.03–2.25), whereas mortality (HR0.86; CI 0.59–1.26) and the incidence of bone fractures (HR1.16; CI 0.86–1.56) were not altered.

Conclusions.

MA is common after kidney transplantation but not associated with an increased frequency of death, graft failure, or bone fractures. Conversely, sodium bicarbonate therapy increased the incidence of graft failure.
Cost-Sensitive Machine Learning Classification for Mass Tuberculosis Screening
Authors: Septiandri Ali Akbar , Aditiawarman  , Tjiong Roy , Burhan Erlina , Shankar Anuraj H.
Published: June 2019

Active screening for Tuberculosis (TB) is needed to optimize detection and treatment. However, current algorithms for verbal screening perform poorly, causing misclassification that leads to missed cases and unnecessary and costly laboratory tests for false positives. We investigated the role of machine learning to improve the predefined one-size-fits-all algorithm used for scoring the verbal screening questionnaire. We present a cost-sensitive machine learning classification for mass tuberculosis screening. We compared score-based classification defined by clinicians to machine learning classification such as SVM-RBF, logistic regression, and XGBoost. We restricted our analyses to data from adults, the population most affected by TB, and investigated the difference between untuned and unweighted classifiers to the cost-sensitive ones. Predictions were compared with the corresponding GeneXpert MTB/Rif results. After adjusting the weight of the positive class to 40 for XGBoost, we achieved 96.64% sensitivity and 35.06% specificity. As such, sensitivity of our identifier increased by 1.26% while specificity increased by 13.19% in absolute value compared to the traditional score-based method defined by our clinicians. Our approach further demonstrated that only 2000 data points were sufficient to enable the model to converge. Our results indicate that even with limited data we can actually devise a better method to identify TB suspects from verbal screening. This approach may be a stepping stone towards more effective TB case identification, especially in primary health centres, and foster better detection and control of TB.
Association of puberty timing with Type 2 diabetes: Systematic review and meta-analysis
Authors: Cheng Tuck Seng , Day Felix R. , Lakshman Rajalakshmi , Ong Ken K.
Published: June 2019

OBJECTIVE

We aimed to systematically review published evidence on the association between puberty timing and Type 2 diabetes or impaired glucose tolerance (T2D/IGT), with and without adjustment for adiposity, and to estimate its potential contribution to the burden of T2D.

RESEARCH DESIGN AND METHODS

We searched PubMed, Medline and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-weighted random-effects meta-analysis was used to pool reported estimates and meta-regression to explore sources of heterogeneity.

RESULTS

Twenty eight observational studies were identified. All assessed age at menarche (AAM) in women (combined N=1,228,306); only one study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was higher per year earlier AAM (relative risk (RR)=0.91, 95% confidence interval (CI)=0.89-0.93, 11 estimates, n=833,529, I2=85.4%) and for early versus later menarche (RR=1.41, 95% CI=1.28-1.55, 23 estimates, n=1,185,444, I2=87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR=0.97 per year, 95% CI=0.95-0.98, 12 estimates, n=852,268, I2=51.8%; early menarche: RR=1.19, 95% CI=1.11-1.28, 21 estimates, n=890,583, I2=68.1%). Associations were stronger among Caucasians than Asians, and in populations with earlier average AAM. The estimated population attributable risk of T2D in UK Caucasians due to early menarche, unadjusted and adjusted for adiposity, was 12.6% (95% CI=11.0-14.3) and 5.1% (95% CI=3.6-6.7), respectively.

CONCLUSIONS

A substantial proportion of T2D in women is attributable to early menarche timing. This will increase in light of global secular trends towards earlier puberty timing.
Maternal Mortality and Women’s Political Participation
Authors: Bhalotra Sonia , Clarke Damian , Gomes Joseph , Venkataramani Atheendar
Published: June 2019

We show that large declines in maternal mortality can be achieved by raising women’s political participation. We estimate that the recent wave of quotas for women in parliament in low income countries has resulted in a 9 to 12% decline in maternal mortality. Among mechanisms are that gender quotas lead to an 8 to 10% increase in skilled birth attendance, a 6 to 12% increase in prenatal care utilization and a 4 to 11% decrease in birth rates.

JEL codes

I14, I15, O15.
Epigenetic prediction of major depressive disorder
Authors: Barbu Miruna C. , Walker Rosie M. , Howard David M. , Evans Kathryn L. , Whalley Heather C. , Porteous David J. , Morris Stewart W. , Deary Ian J. , Marioni Riccardo E. , Clarke Toni-Kim , McIntosh Andrew M.
Published: June 2019

Objective

DNA methylation (DNAm) is associated with environmental risk factors for major depressive disorder (MDD) but has not yet been tested for its ability to discriminate individuals with MDD from unaffected individuals.

Methods

Using penalized regression based on genome-wide CpG methylation, we trained a DNAm risk score of MDD (DNAm-RS) in 1,223 cases and 1,824 controls and tested in a second independent sample of 363 prevalent cases and 1,417 controls. Using DNA from 1,607 unaffected individuals, we tested whether DNAm-RS could discriminate the 190 incident cases of lifetime MDD from the 1,417 individuals who remained unaffected at follow-up.

Results

A weighted linear combination of 196 CpG sites were derived from the training sample to form a DNAm-RS. The DNAm-RS explained 1.75% of the variance in MDD risk in an independent case-control sample and significantly predicted future incident episodes of MDD at follow up (R2=0.52%). DNAm-RS and MDD polygenic risk scores together additively explained 3.99% of the variance in prevalent MDD. The DNAm-RS was also significantly associated with lifestyle factors associated with MDD, including smoking status (β=0.440, p=<2×10−16) and alcohol use (β=0.092, p=9.85×10−5). The DNAm-RS remained significantly associated with MDD after adjustment for these environmental factors (independent association: β=0.338, p=1.17×10−7 association post-adjustment: β=0.081, p=0.0006).

Conclusions

A novel risk score of MDD based on DNAm data significantly discriminated MDD cases from controls in an independent dataset, and controls who would subsequently develop MDD from those who remained unaffected. DNAm-RS captured the effects of exposure to key lifestyle risk factors for MDD, revealing a potential role in risk stratification.
Temporal and spatial limitations in global surveillance for bat filoviruses and henipaviruses
Authors: Becker Daniel J. , Crowley Daniel E. , Washburne Alex D. , Plowright Raina K.
Published: June 2019

Sampling reservoir hosts over time and space is critical to detect epizootics, predict spillover, and design interventions. However, because sampling is logistically difficult and expensive, researchers rarely perform spatiotemporal sampling of many reservoir hosts. Bats are reservoirs of many virulent zoonotic pathogens such as filoviruses and henipaviruses, yet the highly mobile nature of these animals has limited optimal sampling of bat populations. To quantify the frequency of temporal sampling and to characterize the geographic scope of bat virus research, we here collated data on filovirus and henipavirus prevalence and seroprevalence in wild bats. We used a phylogenetically controlled meta-analysis to next assess temporal and spatial variation in bat virus detection estimates. Our analysis shows that only one in four bat virus studies report data longitudinally, that sampling efforts cluster geographically (e.g., filovirus data are available across much of Africa and Asia but are absent from Latin America and Oceania), and that sampling designs and reporting practices may affect some viral detection estimates (e.g., filovirus seroprevalence). Within the limited number of longitudinal bat virus studies, we observed high heterogeneity in viral detection estimates that in turn reflected both spatial and temporal variation. This suggests that spatiotemporal sampling designs are essential to understand how zoonotic viruses are maintained and spread within and across wild bat populations, which in turn could help predict and preempt risks of zoonotic viral spillover.
Physical activity and screen time in children who survived cancer – A report from the Swiss Childhood Cancer Survivor Study
Authors: Schindera Christina , Weiss Annette , Hagenbuch Niels , Otth Maria , Diesch Tamara , von der Weid Nicolas , Kuehni Claudia E. ,   for the Swiss Pediatric Oncology Group (SPOG) Scientific Committee
Published: June 2019

Background

Physical activity (PA) can reduce the risk of chronic adverse health conditions in childhood cancer survivors. We examined physical activity and sedentary screen time behavior in a nationwide study in Switzerland.

Procedures

The Swiss Childhood Cancer Survivor Study sent questionnaires to parents of all Swiss resident ≥5 year-survivors diagnosed 1995–2010. We assessed physical activity including compulsory school sport, recreational sport, commuting to school, and time spent with screen media in those aged 5–15 years, and compared results to international recommendations.

Results

We included 766 survivors with a median age at diagnosis of 2.8 (interquartile range 1.4–5.0) years and a median age at study of 12.5 (10.0–14.3) years. Median PA time was 7.3 (4.8–10.0) hours/week and median screen time 1.4 (0.8–2.0) hours/day. Compulsory school sport hours and walking or cycling to school contributed significantly to total PA. 55% of survivors met PA and 68% screen time recommendations. PA was lower for children living in regions of Switzerland speaking French or Italian compared to German, and for those who had a relapse or musculoskeletal/neurological conditions. Screen time was higher in males, and children with lower parental education and a migration background.

Conclusions

PA and sedentary screen watching were associated with social factors and PA also with clinical risk factors. Structural preventions that afford active commuting to school and sufficient school sport are essential, as is counselling vulnerable survivor groups such as those with musculoskeletal and neurological problems, and those who have had a relapse.
Retrograde mitochondrial transport is essential for mitochondrial homeostasis in neurons
Authors: Mandal Amrita , Pinter Katherine , Mosqueda Natalie , Beirl Alisha , Lomash Richa Madan , Won Sehoon , Kindt Katie S , Drerup Catherine M
Published: June 2019

Mitochondrial transport in neurons is essential for forming and maintaining axonal projections. While much is known about anterograde mitochondrial movement, the function of retrograde mitochondrial motility in neurons was unknown. We investigated the dynamics and utility of retrograde mitochondrial transport. Using long-term tracking of mitochondria in vivo, we found mitochondria in axon terminals turnover within hours via retrograde transport. Mitochondria do not return to the cell body solely for degradation; rather, mitochondria use bidirectional transport to redistribute themselves throughout the neuron. Disruption of retrograde mitochondrial transport severely depletes the cell body of mitochondria and impacts mitochondrial health throughout the cell. Altered mitochondrial health correlates with decreased synaptic activity. Using proteomics, we provide evidence that retrograde mitochondrial movement functions to maintain the organelle’s proteome. Together, our work demonstrates that mitochondrial retrograde transport is essential for the maintenance of a homeostatic population of mitochondria in neurons and consequently effective synaptic activity through promoting mitochondrial protein turnover.
The mutational footprints of cancer therapies
Authors: Pich Oriol , Muiños Ferran , Lolkema Martijn Paul , Steeghs Neeltje , Gonzalez-Perez Abel , Lopez-Bigas Nuria
Published: June 2019

Some cancer therapies damage DNA and cause mutations both in cancer and healthy cells of the patient1. These therapy-induced mutations may underlie some of the long-term and late side effects of the treatment, such as mental disabilities, organ toxicities and secondary neoplasms. Currently we ignore the mutation pattern and burden caused by different cancer treatments. Here we identify mutational signatures, or footprints of six widely-used anti-cancer therapies with the study of whole-genomes from more than 3500 metastatic tumors originated in different organs. These include previously known and new mutational signatures generated by platinum-based drugs, and a novel signature of treatment with nucleoside metabolic inhibitors. Exploiting these mutational footprints, we estimate the contribution of different treatments to the mutation burden of tumors and their risk of causing coding and likely driver mutations in the genome. In summary, the mutational footprints identified here open a window to precisely appraise the mutational risk of different cancer therapies to understand their late side effects.
Functional convergence of autonomic and sensorimotor processing in the lateral cerebellum
Authors: Romano Vincenzo , Reddington Aoibhinn L. , Cazzanelli Silvia , Negrello Mario , Bosman Laurens W.J. , De Zeeuw Chris I.
Published: June 2019

The cerebellum is involved in control of voluntary and autonomic rhythmic behaviors, yet it is largely unclear to what extent it coordinates these in a concerted action. Here, we studied Purkinje cell activity during unperturbed and perturbed respiration in cerebellar lobules simplex, crus 1 and 2. During unperturbed (eupneic) respiration complex spike and simple spike activity encoded respiratory activity, the timing of which corresponded with ongoing sensorimotor feedback. Instead, upon whisker stimulation mice concomitantly accelerated their simple spike activity and inspiration in a phase-dependent manner. Moreover, the accelerating impact of whisker stimulation on respiration could be mimicked by optogenetic stimulation of Purkinje cells and prevented by cell-specific genetic modification of their AMPA receptors that hampered increases in simple spike firing. Thus, the impact of Purkinje cell activity on respiratory control is context- and phase-dependent, suggesting a coordinating role for the cerebellar hemispheres in aligning autonomic and sensorimotor behaviors.
Neuromodulatory selection of motor neuron recruitment patterns in a visuomotor behavior increases speed
Authors: Jha Urvashi , Thirumalai Vatsala
Published: June 2019

Animals generate locomotion at different speeds to suit their behavioral needs. Spinal circuits generate locomotion at these varying speeds by sequential activation of different spinal interneurons and motor neurons. Larval zebrafish can generate slow swims for prey capture and exploration by activation of secondary motor neurons and much faster and vigorous swims during escapes and struggles via the additional activation of primary motor neurons. Neuromodulators are known to alter motor output of spinal circuits yet their precise role in speed regulation is not understood well. Here, in the context of optomotor response (OMR), an innate, evoked locomotor behavior, we show that dopamine (DA) provides an additional layer to regulation of swim speed in larval zebrafish. Activation of D1-like receptors increases swim speed during OMR in free-swimming larvae. By analysing tail bend kinematics in head-restrained larvae, we show that the increase in speed is actuated by larger tail bends. Whole cell patch clamp recordings from motor neurons reveal that during OMR, typically only secondary motor neurons are active while primary motor neurons are quiescent. Activation of D1-like receptors increases motor drive from secondary motor neurons by decreasing spike threshold and latency. In addition, D1-like receptor activation enhances excitability and recruits quiescent primary motor neurons. Our findings provide an example of neuromodulatory reconfiguration of spinal motor neuron speed modules such that members are selectively recruited and motor drive is increased to effect changes in locomotor speed.

Highlights

Zebrafish larvae generate swims of increased speed during optomotor response when D1-like receptors are activated.

D1-like receptor activation increases the extent of tail bending during forward swims and turns resulting in increased swim speed.

Neuromodulation via D1-like receptors increases motor drive by enhancing excitability of ‘slow’ motor neurons. In addition, D1-like receptor activation recruits quiescent ‘fast’ motor neurons to increase swim speed.

This demonstrates neuromodulatory selection of motor neurons belonging to different ‘speed’ modules to alter swimming behavior.

Graphical abstract
How does grasshopperOxya chinensisrespond to the artificially infected bacteria?
Authors: Zhang Xiaomin , Zhang Keshi
Published: June 2019

Oxya chinensisis one of the most widespread grasshopper species found in China and one of the most common pests against rice. Due to the importance of haemocytes in insect immunity and limited information on the haemocytes ofO. chinensis, their haemocytes were examined in detail. The cellular response of the grasshopper was challenged with bacteriaEscherichia coli,Staphylococcus aureusandBacillus subtilis. The morphology of the haemocytes was illustrated by the use of light, scanning electron and transmission electron microscopy, where different morphological varieties of haemocytes were observed. Granulocytes and plasmatocytes responded to the challenged bacteria by phagocytosis. The histochemical staining has indicated the presence of acid phosphatase in plasmatocytes and granulocytes. Non-phagocytic prohemocytes and vermicytes were noticed, but their functions in the circulation are unclear. Our results demonstrate an essential role of plasmatocytes and granulocytes in the innate immunity ofO. chinensis. Insect haemocytes play a crucial role in cellular immunity, and further research is needed for a comprehensive understanding.

Summary statement

The cellular response was used byOxya chinensisagainst the bacterial challenges where two types of haemocytes shared the duty of phagocytosis.
Di-Ras2 Promotes Renal Cell Carcinoma Formation by Activating the MAPK Pathway in the Absence of VHL
Authors: Rao Hanyu , Li Xuefeng , Liu Min , Liu Jing , Li Xiaoxue , Xu Jin , Li Li , Gao Wei-Qiang
Published: June 2019

Clear cell renal cell carcinoma (ccRCC) is one of the most common and lethal human urological malignancies in the world. The pathological drivers for ccRCC are still poorly understood. One of them is the Ras family of small GTPases that function as “molecular switches” in many diseases including ccRCC. Among them, Di-Ras2 encodes a 26-kDa GTPase that shares 60% homology to Ras and Rap. Yet little is known about the biological function(s) of Di-Ras2. In this study, we found that Di-Ras2 was upregulated in ccRCC, and promoted the proliferation, migration and invasion of human ccRCC cells in the absence of von Hippel-Lindau (VHL). Mechanistically, Di-Ras2 induces and regulates ccRCC formation by modulating phosphorylation of the downstream effectors and activating the MAPK signaling pathway. Moreover, Di-Ras2 interacts with E3 ubiquitin ligase, VHL, which facilitates the ubiquitination and degradation of Di-Ras2. Together, these results indicate a potential function of Di-Ras2 as an oncogene and biomarker in ccRCC, and these data provide a new perspective of the relationship between VHL and the MAPK pathway in ccRCC tumorigenesis.
A limbic circuit selectively linking active escape to food suppression
Authors: Azevedo Estefania P. , Tan Bowen , Pomeranz Lisa E. , Ivan Violet , Fetcho Robert N. , Schneeberger Marc , Doerig Katherine R. , Liston Conor , Friedman Jeffrey M. , Stern Sarah A.
Published: June 2019

Stress and anxiety are precipitating factors for eating disorders, but the neural basis linking stress to alterations in feeding is not well understood. Here we describe a novel population of stress-responsive neurons in the lateral septum (LS) of mice that express neurotensin (LSNTS) in a sexually dimorphic, estrous cycle-dependent manner. We used in vivo imaging to show that LSNTS neurons are activated by stressful experiences when flight is a viable option, but not by a stressful experience associated with freezing or immobility. LSNTS activation leads to a decrease of food intake and body weight in mice, without altering locomotion or other behaviors associated with anxiety. Molecular profiling of LSNTS neurons showed that these neurons co-express Glp1r (glucagon-like peptide 1 receptor), and both pharmacologic and genetic manipulations of Glp1r signaling in the LS recapitulates the behavioral effects of LSNTS activation. Finally, we mapped the outputs of LSNTS neurons and show that activation of LSNTS nerve terminals in the lateral hypothalamus (LH), a well-established feeding center, also decrease food intake. Taken together, these results show that LSNTS neurons link stress and anorexia via effects on hypothalamic pathways regulating food intake.
The emergence of successfulStreptococcus pyogeneslineages through convergent pathways of capsule loss and recombination directing high toxin expression
Authors: Turner Claire E. , Holden Matthew T. G. , Blane Beth , Horner Carolyne , Peacock Sharon J. , Sriskandan Shiranee
Published: June 2019

Gene transfer and homologous recombination inStreptococcus pyogeneshas the potential to trigger the emergence of pandemic lineages, as exemplified by lineages ofemm1 andemm89 that emerged in the 1980s and 2000s respectively. Although near-identical replacement gene transfer events in thenga(NADase) andslo(Streptolysin O) locus conferring high expression of these toxins underpinned the success of these lineages, extension to otheremm-genotype lineages is unreported. The emergentemm89 lineage was characterised by five regions of homologous recombination additional tonga/slo, including complete loss of the hyaluronic acid capsule synthesis locushasABC,a genetic trait replicated in two other leadingemmtypes and recapitulated by otheremmtypes by inactivating mutations. We hypothesised that other leading genotypes may have undergone a similar recombination events. We analysed a longitudinal dataset of genomes from 344 clinical invasive disease isolates representative of locations across England, dating from 2001 to 2011, and an international collection ofS. pyogenesgenomes representing 54 different genotypes, and found frequent evidence of recombination events at thenga-slolocus predicted to confer higher toxin expression. We identified multiple associations between recombination at this locus and inactivating mutations withinhasA/B,suggesting convergent evolutionary pathways in successful genotypes. This included common genotypesemm28 andemm87. The combination of no or low capsule, and high expression ofngaandslo,may underpin the success for many emergentS. pyogeneslineages of different genotypes, triggering new pandemics and could change the wayS. pyogenescauses disease.

Importance

Streptococcus pyogenesis a genetically diverse pathogen, with over 200 different genotypes defined byemmtyping, but only a minority of these genotypes are responsible for majority of human infection in high income countries. Two prevalent genotypes associated with disease rose to international dominance following recombination of a toxin locus that conferred increased expression. Here, we found that recombination of this locus and promoter has occurred in other diverse genotypes, events that may allow these genotypes to expand in the population. We identified an association between the loss of hyaluronic acid capsule synthesis and high toxin expression, which we propose may be associated with an adaptive advantage. AsS. pyogenespathogenesis depends both on capsule and toxin production, new variants with altered expression may result in abrupt changes in the molecular epidemiology of this pathogen in the human population over time.
Validation and characterisation of a wheat GENIE3 network using an independent RNA-Seq dataset
Authors: Harrington Sophie A. , Backhaus Anna E. , Singh Ajit , Hassani-Pak Keywan , Uauy Cristobal
Published: June 2019

Gene regulatory networks are powerful tools which facilitate hypothesis generation and candidate gene discovery. However, the extent to which the network predictions are biologically relevant is often unclear. Recently, as part of an analysis of the RefSeqv1.0 wheat transcriptome, a GENIE3 network which predicted targets of wheat transcription factors was produced. Here we have used an independent and publicly-available RNA-Seq dataset to validate the predictions of the wheat GENIE3 network for the senescence-regulating transcription factor NAM-A1 (TraesCS6A02G108300). We re-analysed the RNA-Seq data against the RefSeqv1.0 genome and identified a de novo set of differentially expressed genes (DEGs) between the wild-type and nam-a1 mutant which recapitulated the known role of NAM-A1 in senescence and nutrient remobilisation. We found that the GENIE3-predicted target genes of NAM-A1 overlap significantly with the de novo DEGs, more than would be expected for a random transcription factor. Based on high levels of overlap between GENIE3-predicted target genes and the de novo DEGs, we also identified a set of candidate senescence regulators. We then explored genome-wide trends in the network related to polyploidy and homoeolog expression levels and found that only homoeologous transcription factors are likely to share predicted targets in common. However, homoeologs in dynamic triads, i.e. with higher variation in homoeolog expression levels across tissues, are less likely to share predicted targets than stable triads. This suggests that homoeologs in dynamic triads are more likely to act on distinct pathways. This work demonstrates that the wheat GENIE3 network can provide biologically-relevant predictions of transcription factor targets, which can be used for candidate gene prediction and for global analyses of transcription factor function. The GENIE3 network has now been integrated into the KnetMiner web application, facilitating its use in future studies.
The anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Beclin1/Atg6-mediated lethal autophagy in polyploid cells
Authors: Zhang Jing , Zhang Shenqiu , Wu Fachi , Shi Qiong , Allen Thaddeus , You Fengming , Yang Dun
Published: June 2019

Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by confering more or less potency in the killing of tumor cells. To identify such modifers, we utilized isogenic cell lines to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoposis. We found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a panaurora kinase inhibitor, VX-680. We demonstrate that this suppression stems from the rescue of autophagic cell death, specifically of multinucleated cells, rather than a general inhibition of apoptosis. Bcl-2 inhibits VX-680-induced death of polyploid cells by interacting with the autophagy protein Beclin1/Atg6 and rescue requires localization of Bcl-2 to the endoplasmic reticulum. These findings expand on previous conclusions that autophagic death of polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs.
GraphDTA: Predicting drug–target binding affinity with graph neural networks
Authors: Nguyen Thin , Le Hang , Quinn Thomas P. , Nguyen Tri , Le Thuc Duy , Venkatesh Svetha
Published: June 2019

The development of new drugs is costly, time consuming, and often accompanied with safety issues. Drug repurposing can avoid the expensive and lengthy process of drug development by finding new uses for already approved drugs. In order to repurpose drugs effectively, it is useful to know which proteins are targeted by which drugs. Computational models that estimate the interaction strength of new drug--target pairs have the potential to expedite drug repurposing. Several models have been proposed for this task. However, these models represent the drugs as strings, which is not a natural way to represent molecules. We propose a new model called GraphDTA that represents drugs as graphs and uses graph neural networks to predict drug--target affinity. We show that graph neural networks not only predict drug--target affinity better than non-deep learning models, but also outperform competing deep learning methods. Our results confirm that deep learning models are appropriate for drug--target binding affinity prediction, and that representing drugs as graphs can lead to further improvements.

Availability of data and materials

The proposed models are implemented in Python. Related data, pre-trained models, and source code are publicly available at https://github.com/thinng/GraphDTA. All scripts and data needed to reproduce the post-hoc statistical analysis are available from https://doi.org/10.5281/zenodo.3603523.

Contact

Thin.Nguyen@deakin.edu.au
SmartRNASeqCaller: improving germline variant calling from RNAseq
Authors: Bosio Mattia , Valencia Alfonso , Capella-Gutierrez Salvador
Published: June 2019

Background

Transcriptomics data, often referred as RNA-Seq, are increasingly being adopted in clinical practice due to the opportunity to answer several questions with the same data - e.g. gene expression, splicing, allele-specific expression even without matching DNA. Indeed, recent studies showed how RNA-Seq can contribute to decipher the impact of germline variants. These efforts allowed to dramatically improved the diagnostic yield in specific rare disease patient cohorts. Nevertheless, RNA-Seq is not routinely adopted for germline variant calling in the clinic. This is mostly due to a combination of technical noise and biological processes that affect the reliability of results, and are difficult to reduce using standard filtering strategies.

Results

To provide reliable germline variant calling from RNA-Seq for clinical use, such as for mendelian diseases diagnosis, we developed SmartRNASeqCaller: a Machine Learning system focused to reduce the burden of false positive calls from RNA-Seq. Thanks to the availability of large amount of high quality data, we could comprehensively train SmartRNASeqCaller using a suitable features set to characterize each potential variant.

The model integrates information from multiple sources, capturing variant-specific characteristics, contextual information, and external sources of annotation. We tested our tool against state-of-the-art workflows on a set of 376 independent validation samples from GIAB, Neuromics, and GTEx consortia. SmartRNASeqCaller remarkably increases precision of RNA-Seq germline variant calls, reducing the false positive burden by 50% without strong impact on sensitivity. This translates to an average precision increase of 20.9%, showing a consistent effect on samples from different origins and characteristics.

Conclusions

SmartRNASeqCaller shows that a general strategy adopted in different areas of applied machine learning can be exploited to improve variant calling. Switching from a naïve hard-filtering schema to a more powerful, data-driven solution enabled a qualitative and quantitative improvement in terms of precision/recall performances. This is key for the intended use of SmartRNASeqCaller within clinical settings to identify disease-causing variants.
Widespread positive selection for mRNA secondary structure at synonymous sites in domesticated yeast
Authors: Yu Minghao , Guo Wenna , Wang Qiang , Chen Jian-Qun
Published: June 2019

mRNA secondary structure assumes a critical role in gene regulation, especially for translational efficiency. Previous studies have a growing appreciation of purifying selection for the conserved mRNA structure across lineages of different species. However, the effect of mRNA structure on positive evolution remains unclear. Here, we construct a large-scale dataset of single nucleotide polymorphisms (SNPs) at synonymous sites in the population ofSaccharomyces cerevisiae, combined with the experimental assessment of mRNA structure, and perform empirical population genetics data analysis through unfolded site-frequency spectra. Our results suggest that functional mRNA stem drives faster evolution of increasing GC contents itself with the purpose of regulating translational speed, which is greatly influenced by length. At the synonymous site without codon usage bias, this kind of positive selection still exists. Furthermore, mRNA secondary structure is subject to positive selection widespread among the yeast genome, particularly related to mitochondria activities, which is possibly aimed to achieve a balance between cellular respiration and alcoholic fermentation precisely at a non-protein level. It is conducive to the adaption of the dramatic environment alterations from wild to man-made environments during the domestication.