bluuebunny/crossref_metadata_2025 huggingface dataset:
COMBINED VITRECTOMY WITH INTRAVITREAL DEXAMETHASONE IMPLANT FOR REFRACTORY MACULAR EDEMA SECONDARY TO DIABETIC RETINOPATHY, RETINAL VEIN OCCLUSION, AND NONINFECTIOUS POSTERIOR UVEITIS
Authors: Pang John Paul , Son Gisung , Yoon Young Hee , Kim June-Gone , Lee Joo Yong
Published: October 2018

Purpose:

To compare the efficacy of intraoperative intravitreal dexamethasone implant for macular edema secondary to diabetic retinopathy (DME), retinal vein occlusion (RVO), and noninfectious posterior uveitis.

Methods:

A retrospective review of 62 patients (29 men and 33 women; mean age 51.19 ± 14.41 years; 65 eyes) was performed. Best-corrected visual acuity (in logarithm of the minimal angle of resolution), central foveal thickness, intraocular pressure, and postoperative edema-free period were postoperatively assessed up to 1 year. The preoperative and postoperative numbers of other intravitreal injections needed were compared.

Results:

Best-corrected visual acuity gradually improved in the DME group (from 0.87 to 0.51) but failed to improve from Month 3 onward in the RVO and uveitis groups. Central foveal thickness decreased in all groups, especially in the DME group (from 550.93 to 338.10 μm). Edema-free period was longest in the DME group (19.34 ± 15.12 months), followed by the uveitis (12.91 ± 7.85 months) and RVO (8.50 ± 8.76 months) groups. Subjects in the uveitis group used more intraocular pressure–lowering agents (1.00 ± 1.27) than those in the DME (0.13 ± 0.49) and RVO (0.36 ± 0.79) groups. Increased intraocular pressure events were most frequent in postoperative Week 1, especially in the uveitis group.

Conclusion:

Vitrectomy combined with intravitreal dexamethasone implant for DME, RVO, and noninfectious posterior uveitis had a favorable clinical outcome.
EYES WITH SUBRETINAL DRUSENOID DEPOSITS AND NO DRUSEN
Authors: Spaide Richard F. , Yannuzzi Lawrence , Freund K. Bailey , Mullins Robert , Stone Edwin
Published: October 2018

Purpose:

To investigate the macular changes over time in eyes containing subretinal drusenoid deposits (also known as pseudodrusen) with no drusen >63 µm.

Methods:

A consecutive series of patients were examined with color fundus photography, optical coherence tomography, and autofluorescence imaging with fluorescein angiography used as necessary. Exclusionary criteria included macular neovascularization, history of retinal surgery, pseudoxanthoma elasticum, and drusen >63 µm.

Results:

There were 85 eyes of 54 patients. The mean age at baseline was 83.6 (±7.8) years, and there were 17 men. The mean follow-up was 5.0 (±2.9) years. At initial optical coherence tomography examination, 12 eyes had extrafoveal atrophy and 17 eyes had vitelliform deposits, which were yellowish white subretinal collections that showed intense hyperautofluorescence. During follow-up, 11 eyes lost vitelliform material. After the disappearance of small deposits, focal hyperpigmentation remained. Loss of larger deposits was associated with noteworthy sequela; six developed subfoveal atrophy and one macular neovascularization close to regressing vitelliform material. Subfoveal geographic atrophy developed in four other eyes without vitelliform material by extension from areas of extrafoveal atrophy. Macular neovascularization developed in seven eyes over follow-up. The CFH Y402H and ARMS2 A69S allele frequencies were 57% and 48.9%, respectively, which is similar to a group of age-related macular degeneration controls. One patient had a novel PRPH2 mutation, but did not have a vitelliform deposit; the remainder had a normal PRPH2 and BEST1 coding sequences.

Conclusion:

Eyes with subretinal drusenoid deposits and no drusen >63 mm have significant risk for the development of both neovascularization and geographic atrophy, the fundamental components of late age-related macular degeneration. An intermediate step in some eyes was the development of a vitelliform deposit, an entity not traditionally associated with age-related macular degeneration, but in these patients, the material seemed to be an important component of the disease pathophysiology. This vitelliform deposit was not associated with genetic markers for pattern dystrophy or Best disease.
Dialysis catheters in the ICU: selection, insertion and maintenance
Authors: Girardot Thibaut , Monard Céline , Rimmelé Thomas
Published: October 2018

Purpose of review

Choosing the best catheter for renal replacement therapy (RRT) is not an easy task. Beyond catheter length, many of its properties can influence effectiveness of the RRT session. Maintenance between sessions, particularly the locking solution, also impacts catheter lifespan and infection rates.

Recent findings

Many innovations in dialysis catheters have been proposed by the industry over the past decade, including the material used, the shape of the lumens and the position of the inflow and outflow holes. Impregnated catheters have also been developed to prevent catheter-related infections. Many locking solutions are available, either for maintaining catheter patency or for preventing infections.

Although studies conducted in the specific context of the ICU are still scarce, some conclusions can be drawn. Catheter length must be adapted to the insertion site to reach an area of high blood flow. Kidney-shape lumens appear to be less thrombogenic and seem to prevent catheter dysfunction. Catheter tip and lumen holes also affect catheter function. For catheter locking, 4% citrate appears nowadays as one of the best options, but taurolidine-based solutions are also interesting.
Noninvasive ventilation as acute therapy
Authors: Thille Arnaud W. , Frat Jean-Pierre
Published: October 2018

Purpose of review

Noninvasive ventilation (NIV) is widely used in ICU patients to treat or to prevent acute respiratory failure. Whereas its physiological effects are clearly beneficial in hypercapnic patients, it could be deleterious in hypoxemic patients without hypercapnia.

Recent findings

NIV should be cautiously used in patients with de-novo respiratory failure, the vast majority of whom meet the criteria for acute respiratory distress syndrome. Spontaneous breathing with high tidal volumes may worsen lung injury in these patients, and recent findings suggest that NIV may increase the risk of mortality. Even though high-flow oxygen therapy is increasingly applied in this context, NIV remains recommended for management of immunocompromised patients with acute respiratory failure. NIV should be the first-line oxygenation strategy in patients with acute hypercapnic respiratory failure when pH is equal to or below 7.35. Prophylactic NIV prevents respiratory failure after extubation of patients at high risk of reintubation.

Most previous studies have compared NIV with standard oxygen, and recent recommendations have been established from these findings. Given the growing use of high-flow oxygen therapy, new studies are needed to compare NIV versus high-flow oxygen therapy so as to better define the appropriate indications for each treatment.
Perioperative management of obese patient
Authors: Bazurro Simone , Ball Lorenzo , Pelosi Paolo
Published: October 2018

Purpose of review

The volume of bariatric and nonbariatric surgical procedures on obese patients is dramatically increasing worldwide over the past years. In this review, we discuss the physiopathlogy of respiratory function during anesthesia in obese patients, the stratification of perioperative risk to develop intraoperative and postoperative pulmonary complications, the optimization of airway management, and perioperative ventilation, including postoperative respiratory assistance.

Recent findings

Scores have been proposed to stratify the risk of surgical patients, some of which were specifically developed for obese patients. Most scores identify obstructive sleep apnea and elevated BMI as independent risk factors. Obese patients might be at risk of difficult intubation and mask ventilation, and also of developing postoperative pulmonary complications. Intraoperative ventilation settings affect clinical outcome, but the optimal ventilation strategy is still to be determined. Opioid-free regimens are being widely investigated. Postoperative monitoring and respiratory assistance are necessary in selected patients. Early mobilization and physiotherapy are mandatory.

Obese patients are at higher risk of perioperative complications, mainly associated with those related to the respiratory function. An appropriate preoperative evaluation, intraoperative management, and postoperative support and monitoring is essential to improve outcome and increase the safety of the surgical procedure.
How to optimize critical care resources in surgical patients: intensive care without physical borders
Authors: Pelosi Paolo , Ball Lorenzo , Schultz Marcus J.
Published: October 2018

Purpose of review

Timely identification of surgery patients at risk of postoperative complications is important to improve the care process, including critical care. This review discusses epidemiology and impact of postoperative complications; prediction scores used to identify surgical patients at risk of complications, and the role of critical care in the postoperative management. It also discusses how critical care may change, with respect to admission to the ICU.

Recent finding

Optimization of postoperative outcome, next to preoperative and intraoperative optimization, consists of using risk scores to early identify patients at risk of developing complications. Critical care consultancy should be performed in the ward after surgery, if necessary. ICUs could work at different levels of intensity, but remain preferably multidisciplinary, combining care for surgical and medical patients. ICU admission should still be considered for those patients at very high risk of postoperative complications, and for those receiving complex or emergency interventions.

To optimize critical care resources for surgery patients at high risk of postoperative complications, the care process should not only include critical care and monitoring in ICUs, but also strict monitoring in the ward. Prediction scores could help to timely identify patients at risk. More intense care (monitoring) outside the ICU could improve outcome. This concept of critical care without borders could be implemented in the near future to optimize the local resources and improve patient safety. Predict more, do less in ICUs, and more in the ward.
Major surgery and the immune system: from pathophysiology to treatment
Authors: Shankar Hari Manu , Summers Charlotte
Published: October 2018

Purpose of review

The purpose of this review is to provide an overview of the immune response to major surgery, and the ways in which it may be modulated to improve postoperative outcomes.

Recent findings

Data from patients who have undergone a variety of tissue injuries (surgery, burns, sepsis, trauma) have shown the presence of a conserved ‘genomic storm’ that alters the leukocyte transcriptome, with upregulation of the innate immune response and concomitant downregulation of the adaptive immune response. The innate and adaptive immune systems are often regarded largely distinct. However, more recent evidence suggests there are critical connections between the two arms of the immune response, whereby innate immune cells are able to suppress the adaptive response.

The immune system is critical to the host response to tissue injury occurring due to surgery. However, the physiological processes required to resolve the surgical insult can also contribute to sequelae such as cognitive decline, pneumonia and acute kidney injury. Our understanding of the immune pathogenesis underlying these complications is improving, leading to interest in the development of immunomodulatory therapies, which aim to permit host defence whilst ameliorating postoperative complications.
Anti-Müllerian hormone as a predictor of reproductive potential
Authors: Hawkins Bressler Leah , Steiner Anne
Published: October 2018

Purpose of review

Anti-Müllerian hormone (AMH), a marker of ovarian reserve, declines over a woman's reproductive lifespan. AMH is highly correlated with a woman's age and number of primordial ovarian follicles, and has been shown to predict time to menopause in women in their 40s. For these reasons, it was assumed that AMH levels could predict a woman's reproductive potential or serve as a ‘fertility test’. Recently, studies have sought to determine the association between AMH and fertility.

Recent findings

Although a small, prospective, time-to-pregnancy study of 98 women suggested that an AMH level less than 0.7 ng/ml was associated with lower day-specific probabilities of conception, the follow-up, larger cohort did not identify an association with AMH and fecundability. Women with AMH values less than 0.7 ng/ml had similar pregnancy rates after 12 cycles of attempting to conceive as women with normal AMH values after adjusting for age. Four additional studies, including a secondary analysis of the NICHD EAGER trial including over 1200 women confirmed these findings.

Although AMH is a marker of ovarian reserve, existing literature does not support the use of AMH as a marker of reproductive potential in the general population.
Current clinical applications of antimullerian hormone
Authors: Merlotti Lindsay , Kuohung Wendy , Rinehart John
Published: October 2018

Purpose of review

Determine if literature supports the use of anti-Müllerian hormone (AMH) as a useful biomarker of reproductive potential when cumulative live birth rates (CLBRs) per retrieval are used as the outcome variable.

Recent findings

Advances in technology used in in-vitro fertilization (IVF) permit the use of single embryo transfer to achieve expected pregnancy success rates. Many IVF cycles result in the creation of more than a single embryo suitable for transfer per oocyte retrieval. Cryopreservation permits subsequent use of other embryos with no loss in total reproductive potential from single retrievals. Therefore, an emerging concept in IVF is the CLBR per retrieval as an indicator of the patient's reproductive potential. Using the total reproductive potential from a single retrieval may help patients decide on IVF. As such, any predictor of success that relies upon the live birth rate for a single transfer, as opposed to CLBR per retrieval, is inadequate to estimate the true reproductive potential for patient. AMH has been proposed as a biomarker for reproductive potential, but most studies have correlated an AMH value to a single embryo transfer.

A more appropriate way to use AMH levels may be to correlate the AMH with CLBR per retrieval. AMH may thus prove to be a useful biomarker when counseling patients about what to expect from their treatment.
Anti-müllerian hormone in the pathophysiology and diagnosis of polycystic ovarian syndrome
Authors: Dumont Agathe , Robin Geoffroy , Dewailly Didier
Published: October 2018

Purpose of review

Polycystic ovarian syndrome (PCOS) is the most common cause of chronic anovulation and hyperandrogenism in young women and represents a true public health concern and an economic burden.

Recent findings

The pathophysiology of PCOS is still not fully understood, but progresses have been made and the relationships between anti mullerian hormone (AMH), follicle stimulating hormone, luteinizing hormone, E2 and androgens have been explored. The follicle excess plays a central role in the syndrome and AMH is definitively a major component of this phenomena.

The aim of this chapter is to present the recent work studying the role of AMH in the pathophysiology of PCOS and to discuss the improvement that serum AMH assay brings in the diagnosis of PCOS.
Use of bone turnover markers in the management of osteoporosis
Authors: Jain Sumeet , Camacho Pauline
Published: October 2018

Purpose of review

Osteoporosis is a common public health problem that is often undertreated and underdiagnosed. The clinical management of osteoporosis is often reactionary to devastating fracture events. Bone turnover markers may improve the ease and rapidity at which osteoporosis is monitored and treated. Bone turnover markers are biochemical byproducts of bone formation or bone resorption. The clinical use of bone turnover markers is limited by significant preanalytical variability. Effective interpretation of bone turnover markers requires a detailed understanding of the variables that can affect their responses to osteoporosis treatment and monitoring.

Recent findings

Progress is continuously being made on the standardization of bone turnover markers. The literature on the response of bone turnover markers to unique clinical situations is expanding. Data for evidence-based reference intervals for bone turnover markers has increased. Variables that affect the appropriate timing of lab draws like diurnal variation, postprandial status, exercise and alcohol use have been described. Studies examining the expected response of bone turnover markers to treatments of osteoporosis and other medications that affect bone health continue to increase.

Bone turnover markers have clinical utility in the comprehensive evaluation of osteoporosis. When interpreted with caution and with a good understanding of their natural variability, bone turnover markers provide information that supplements osteoporosis management and provides useful clinical information about conditions that alter bone turnover.
The role of antimullerian hormone in assessing ovarian damage from chemotherapy, radiotherapy and surgery
Authors: Wong Queenie Ho Yan , Anderson Richard A.
Published: October 2018

Purpose of review

Iatrogenic ovarian damage can occur after chemotherapy, radiotherapy and surgery for cancer as well as for non-malignant conditions. This review describes the effects of such treatment on antimullerian hormone (AMH) and the implications of the fall in AMH in relation to ovarian function and fertility, especially in the era of improved fertility preservation strategies.

Recent findings

The risk of gonadotoxicity differs between chemotherapy regimens. There is growing evidence that pretreatment AMH has prognostic significance for the degree of fall in AMH after treatment, the reversibility of ovarian damage and risk of premature ovarian insufficiency. The accuracy of prediction increases when age is coupled with AMH. The adverse effect of removal of endometriomas is increasingly clear, and AMH pre and post surgery useful is assessing the degree of damage to the ovary. The implications of low AMH after such treatment on natural fertility and reproductive lifespan are less clear. Apart from treatment effects, there are other coexisting conditions that can affect AMH which needs to be taken into consideration during interpretation of AMH before and after treatment.

A fall in AMH in women after gonadotoxic treatment has been consistently described, with variable recovery, the accurate interpretation and clinical application of post-treatment AMH level on reproductive lifespan and fertility prediction needs to be studied in future larger prospective studies with longer follow-up.
Marriage and Gut (Microbiome) Feelings: Tracing Novel Dyadic Pathways to Accelerated Aging
Authors: Kiecolt-Glaser Janice K. , Wilson Stephanie J. , Madison Annelise
Published: October 2018

Within a couple, partners influence each other’s mental and physical health. This review focuses on how couples’ relationships, the partners’ individual and joint vulnerabilities, and their health behaviors influence health through changes in the gut microbiota, metabolism, and immune function. Couples’ shared stressors and emotions and their intertwined lifestyles and routines serve to promote common disease risks in part through parallel changes in their gut microbiotas. Marital discord, stress, and depression have strong bidirectional links, fueling one another. Chronic marital stress and depression can elevate the risk for obesity, metabolic syndrome, and cardiovascular disease by altering resting energy expenditure, insulin production, and triglyceride responses after unhealthy meals. During stressful times, health behaviors typically suffer—and sleep disturbances, poor diets, and sedentary behavior all influence these metabolic pathways while also promoting gut dysbiosis. Dysbiosis increases intestinal permeability (gut leakiness), providing a mechanistic pathway from marital distress and depression to heightened inflammation and accelerated aging. Age-related changes in the gut microbiota’s composition and gut leakiness foster immunosenescence, as well as the progression of inflamm-aging; these age-related risks may be altered by stress and depression, diet, sleep, exercise habits, and developmental shifts in emotion regulation strategies. Consideration of the strong mutual influences that partners have on each other’s mood and health behaviors, as well as the biological pathways that underlie these influences, provides a new way to view marriage’s health implications.
Robot-assisted Minimally Invasive Thoracolaparoscopic Esophagectomy Versus Open Transthoracic Esophagectomy for Resectable Esophageal Cancer
Authors: van der Sluis Pieter C. , van der Horst Sylvia. , May Anne M. , Schippers Carlo , Brosens Lodewijk A. A. , Joore Hans C. A. , Kroese Christiaan C. , Haj Mohammad Nadia , Mook Stella , Vleggaar Frank P. , Borel Rinkes Inne H. M. , Ruurda Jelle P. , van Hillegersberg Richard
Published: October 2018

Background:

The standard curative treatment for patients with esophageal cancer is perioperative chemotherapy or preoperative chemoradiotherapy followed by open transthoracic esophagectomy (OTE). Robot-assisted minimally invasive thoracolaparoscopic esophagectomy (RAMIE) may reduce complications.

Methods:

A single-center randomized controlled trial was conducted, assigning 112 patients with resectable intrathoracic esophageal cancer to either RAMIE or OTE. The primary endpoint was the occurrence of overall surgery-related postoperative complications (modified Clavien-Dindo classification grade 2–5).

Results:

Overall surgery-related postoperative complications occurred less frequently after RAMIE (59%) compared to OTE (80%) [risk ratio with RAMIE (RR) 0.74; 95% confidence interval (CI), 0.57–0.96; P = 0.02]. RAMIE resulted in less median blood loss (400 vs 568 mL, P <0.001), a lower percentage of pulmonary complications (RR 0.54; 95% CI, 0.34–0.85; P = 0.005) and cardiac complications (RR 0.47; 95% CI, 0.27–0.83; P = 0.006) and lower mean postoperative pain (visual analog scale, 1.86 vs 2.62; P < 0.001) compared to OTE. Functional recovery at postoperative day 14 was better in the RAMIE group [RR 1.48 (95% CI, 1.03–2.13; P = 0.038)] with better quality of life score at discharge [mean difference quality of life score 13.4 (2.0–24.7, p = 0.02)] and 6 weeks postdischarge [mean difference 11.1 quality of life score (1.0–21.1; P = 0.03)]. Short- and long-term oncological outcomes were comparable at a medium follow-up of 40 months.

Conclusions:

RAMIE resulted in a lower percentage of overall surgery-related and cardiopulmonary complications with lower postoperative pain, better short-term quality of life, and a better short-term postoperative functional recovery compared to OTE. Oncological outcomes were comparable and in concordance with the highest standards nowadays.
Transoral Robotic Thyroidectomy: Comparison of Surgical Outcomes Between the da Vinci Xi and Si
Authors: Kim Hong Kyu , Kim Hoon Yub , Chai Young Jun , Dionigi Gianlorenzo , Berber Eren , Tufano Ralph P.
Published: October 2018

Introduction:

The surgical outcomes for procedures using da Vinci Xi were compared with those of da Vinci Si in transoral robotic thyroidectomy (TORT).

Materials and Methods:

The medical records were retrospectively reviewed. Patients were classified into 2 groups (da Vinci Xi vs. da Vinci Si) and surgical outcomes were analyzed.

Results:

Each group comprised 58 patients. The postoperative pain scores at operation day 0 were lower, the hospital stays were shorter, and the number of retrieved central lymph nodes in the papillary thyroid carcinoma patients were greater in the Xi group than in the Si group. There were no significant differences between groups in either vocal cord palsy or hypoparathyroidism rates. There were no TORT-specific complications in the Xi group. There was no conversion to endoscopic or conventional open thyroid surgery in both groups.

Conclusions:

TORT could be performed safely with both da Vinci Si and Xi systems.
Modularity speeds up motor learning by overcoming mechanical bias in musculoskeletal geometry
Authors: Hagio Shota , Kouzaki Motoki
Published: October 2018

We can easily learn and perform a variety of movements that fundamentally require complex neuromuscular control. Many empirical findings have demonstrated that a wide range of complex muscle activation patterns could be well captured by the combination of a few functional modules, the so-called muscle synergies. Modularity represented by muscle synergies would simplify the control of a redundant neuromuscular system. However, how the reduction of neuromuscular redundancy through a modular controller contributes to sensorimotor learning remains unclear. To clarify such roles, we constructed a simple neural network model of the motor control system that included three intermediate layers representing neurons in the primary motor cortex, spinal interneurons organized into modules and motoneurons controlling upper-arm muscles. After a model learning period to generate the desired shoulder and/or elbow joint torques, we compared the adaptation to a novel rotational perturbation between modular and non-modular models. A series of simulations demonstrated that the modules reduced the effect of the bias in the distribution of muscle pulling directions, as well as in the distribution of torques associated with individual cortical neurons, which led to a more rapid adaptation to multi-directional force generation. These results suggest that modularity is crucial not only for reducing musculoskeletal redundancy but also for overcoming mechanical bias due to the musculoskeletal geometry allowing for faster adaptation to certain external environments.
Biodiversity, functional redundancy and system stability: subtle connections
Authors: Ulanowicz Robert E.
Published: October 2018

The relationship between biodiversity and functional redundancy has remained ambiguous for over a half-century, likely due to an inability to distinguish between positivist and apophatic (that which is missing) properties of ecosystems. Apophases are best addressed by mathematics that is predicated upon absence, such as information theory. More than 40 years ago, the conditional entropy of a flow network was proposed as a formulaic way to quantify trophic functional redundancy, an advance that has remained relatively unappreciated. When applied to a collection of 25 fully quantified trophic networks, this authoritative index correlates only poorly and transitively with conventional Hill numbers used to represent biodiversity. Despite such a weak connection, the underlying biomass distribution remains useful in conjunction with the qualitative diets of system components for providing a quick and satisfactory emulation of a system's functional redundancy. Furthermore, an information-theoretic cognate of the Wigner Semicircle Rule can be formulated using network conditional entropy to provide clues to the relative stability of any ecosystem under study. The necessity for a balance between positivist and apophatic attributes pertains to the functioning of a host of other living ensemble systems.
A topographic mechanism for arcing of dryland vegetation bands
Authors: Gandhi Punit , Werner Lucien , Iams Sarah , Gowda Karna , Silber Mary
Published: October 2018

Banded patterns consisting of alternating bare soil and dense vegetation have been observed in water-limited ecosystems across the globe, often appearing along gently sloped terrain with the stripes aligned transverse to the elevation gradient. In many cases, these vegetation bands are arced, with field observations suggesting a link between the orientation of arcing relative to the grade and the curvature of the underlying terrain. We modify the water transport in the Klausmeier model of water–biomass interactions, originally posed on a uniform hillslope, to qualitatively capture the influence of terrain curvature on the vegetation patterns. Numerical simulations of this modified model indicate that the vegetation bands arc convex-downslope when growing on top of a ridge, and convex-upslope when growing in a valley. This behaviour is consistent with observations from remote sensing data that we present here. Model simulations show further that whether bands grow on ridges, valleys or both depends on the precipitation level. A survey of three banded vegetation sites, each with a different aridity level, indicates qualitatively similar behaviour.
An E2-ubiquitin thioester-driven approach to identify substrates modified with ubiquitin and ubiquitin-like molecules
Authors: Bakos Gabor , Yu Lu , Gak Igor A. , Roumeliotis Theodoros I. , Liakopoulos Dimitris , Choudhary Jyoti S. , Mansfeld Jörg
Published: October 2018

Covalent modifications of proteins with ubiquitin and ubiquitin-like molecules are instrumental to many biological processes. However, identifying the E3 ligase responsible for these modifications remains a major bottleneck in ubiquitin research. Here, we present an E2-thioester-driven identification (E2~dID) method for the targeted identification of substrates of specific E2 and E3 enzyme pairs. E2~dID exploits the central position of E2-conjugating enzymes in the ubiquitination cascade and providesin vitrogenerated biotinylated E2~ubiquitin thioester conjugates as the sole source for ubiquitinationin extracto. This enables purification and mass spectrometry-based identification of modified proteins under stringent conditions independently of the biological source of the extract. We demonstrate the sensitivity and specificity of E2-dID by identifying and validating substrates of APC/C in human cells. Finally, we perform E2~dID with SUMO inS. cerevisiae, showing that this approach can be easily adapted to other ubiquitin-like modifiers and experimental models.
PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma
Authors: Ogorodnikov Anton , Levin Michal , Tattikota Surendra , Tokalov Sergey , Hoque Mainul , Scherzinger Denise , Marini Federico , Poetsch Ansgar , Binder Harald , Macher-Göppinger Stephan , Tian Bin , Schaefer Michael , Lackner Karl , Westermann Frank , Danckwardt Sven
Published: October 2018

Diversification at the transcriptome 3’end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. Here, we identify extensive transcriptome-3’end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3’end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma associates with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumourigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with important clinical implications. An interactive data repository of transcriptome-wide APA covering >170 RNAis, and an APA-network map with regulatory hubs is provided.
Spatiotemporal patterns of dunlin (Calidris alpina) in continental lakes of the Iberian Peninsula
Authors: Gonçalves M. S. S. , Gil-Delgado J. A. , Gosálvez R. U. , López-Iborra G. M. , Ponz A. , Pons P. S. , Velasco A.
Published: October 2018

Spatiotemporal dynamics may present different levels of regional or local stability, generally attributed to local habitat and landscape factors, reflecting the tolerances and ecological requirements of the populations. In this study, we examined the variations of dunlin abundance and occurrence in twenty-three wetlands of the “La Mancha Húmeda” Biosphere Reserve, central Spain, between October 2010 and July 2017. In addition, we observed the variations of local abundance in the lakes of the Manjavacas lagoon complex, seeking to understand the factors that determine the local movements of the wintering individuals. Eleven lakes had records of dunlin, but most of individuals (ca. 90%) were observed in the Manjavacas Lagoon Complex (Alcahozo and Manjavacas lakes). The preference for this complex associated with temporal variations of abundance between the Alcahozo and Manjavacas lagoons possibly reflects the specific characteristics of the invertebrate community available as prey, especially for the presence of anostracans and copepods. The results of this study are a first step in understanding the factors that lead this species to select continental wetlands as wintering sites.
Adjustment for index event bias in genome-wide association studies of subsequent events
Authors: Dudbridge Frank , Allen Richard J. , Sheehan Nuala A. , Schmidt A. Floriaan , Lee James C. , Jenkins R. Gisli , Wain Louise V. , Hingorani Aroon D. , Patel Riyaz S.
Published: October 2018

Following numerous genome-wide association studies of disease susceptibility, there is increasing interest in genetic associations with prognosis, survival or other subsequent events. Such associations are vulnerable to index event bias, by which selection of subjects according to disease status creates biased associations if common causes of incidence and prognosis are not accounted for. We propose an adjustment for index event bias using the residuals from the regression of genetic effects on prognosis on genetic effects on incidence. Our approach eliminates this bias when direct genetic effects on incidence and prognosis are independent, and otherwise reduces bias in realistic situations. In a study of idiopathic pulmonary fibrosis, we reverse a paradoxical association of the strong susceptibility gene MUCSB with increased survival, suggesting instead a significant association with decreased survival. In re-analysis of a study of Crohn’s disease prognosis, four regions remain associated at genome-wide significance but with increased standard errors.
A Simulation-Based Evaluation of Total-Evidence Dating Under the Fossilized Birth-Death Process
Authors: Luo Arong , Duchêne David A. , Zhang Chi , Zhu Chao-Dong , Ho Simon Y.W.
Published: October 2018

Bayesian molecular dating is widely used to study evolutionary timescales. This procedure usually involves phylogenetic analysis of nucleotide sequence data, with fossil-based calibrations applied as age constraints on internal nodes of the tree. An alternative approach is Bayesian total-evidence dating, which involves the joint analysis of molecular data from present-day taxa and morphological data from both extant and fossil taxa. Part of its appeal stems from the fossilized birth-death process, which provides a model of lineage diversification for the prior on the tree topology and node times. However, total-evidence dating faces a number of considerable challenges, especially those associated with fossil sampling and evolutionary models for morphological characters. We conducted a simulation study to evaluate the performance of total-evidence dating with the fossilized birth-death model. We simulated fossil occurrences and the evolution of nucleotide sequences and morphological characters under a wide range of conditions. Our analyses show that fossil occurrences have a greater influence than the degree of among-lineage rate variation or the number of morphological characters on estimates of node times and the tree topology. Total-evidence dating generally performs well in recovering the relationships among extant taxa, but has difficulties in correctly placing fossil taxa in the tree and identifying the number of sampled ancestors. The method yields accurate estimates of the origin time of the fossilized birth-death process and the ages of the root and crown group, although the precision of these estimates varies with the probability of fossil occurrence. The exclusion of morphological characters results in a slight overestimation of node times, whereas the exclusion of nucleotide sequences has a negative impact on inference of the tree topology. Overall, our results provide a detailed view of the performance of total-evidence dating, which will inform further development of the method and its application to key questions in evolutionary biology.
Targeting translation activity at the ribosome interface with UV-active small molecules
Authors: Kandala Divya T. , Del Piano Alessia , Minati Luca , Clamer Massimiliano
Published: October 2018

Puromycin is a well-known antibiotic that is used to study the mechanism of protein synthesis and to monitor translation efficiency due to its incorporation into nascent peptide chains. However, puromycin effects outside the ribo-some catalytic core remain unexplored. Here, we developed two puromycin analogues (3PB and 3PC) that can efficiently interact with several proteins involved in translation, ribosome function and RNA processing. We biochemically characterized the binding of these analogues and globally mapped the direct small molecule-protein interactions in living cells using clickable and photoreactive puromycin-like probes in combination with in-depth mass spectrometry. We identified a list of proteins that interact with ribosomes during translation (e.g. eEF1A, ENO1 and GRP78) and we addressed possible uses of the probes to sense the activity of protein synthesis and to capture associated RNA. By coupling genome-wide RNA sequencing methods with these molecules, the characterization of unexplored translational control mechanisms will be feasible.
Methyl viologen can affect mitochondrial function in Arabidopsis
Authors: Cui Fuqiang , Brosché Mikael , Shapiguzov Alexey , He Xin-Qiang , Vainonen Julia P. , Leppälä Johanna , Trotta Andrea , Kangasjärvi Saijaliisa , Salojärvi Jarkko , Kangasjärvi Jaakko , Overmyer Kirk
Published: October 2018

Reactive oxygen species (ROS) are key signalling intermediates in plant metabolism, defence, and stress adaptation. The chloroplast and mitochondria are centres of metabolic control and ROS production, which coordinate stress responses in other cell compartments. The herbicide and experimental tool, methyl viologen (MV) induces ROS generation in the chloroplast under illumination, but is also toxic in non-photosynthetic organisms. We used MV to probe plant ROS signalling in compartments other than the chloroplast. Taking a genetic approach inArabidopsis thaliana, we used natural variation, QTL mapping, and mutant studies with MV in the light, but also under dark conditions, when the chloroplast electron transport is inactive. These studies revealed a light-independent MV-induced ROS-signalling pathway, suggesting mitochondrial involvement. Mitochondrial Mn SUPEROXIDE DISMUTASE was required for ROS-tolerance and the effect of MV was enhanced by exogenous sugar, providing further evidence for the role of mitochondria. Mutant and hormone feeding assays revealed roles for stress hormones in organellar ROS-responses. Theradical-induced cell death1mutant, which is tolerant to MV-induced ROS and exhibits altered mitochondrial signalling, was used to probe interactions between organelles. Our studies implicate mitochondria in the response to ROS induced by MV.
Prevotella copri, a potential indicator for high feed efficiency in western steers
Authors: Brooke Charles G. , Najafi Negeen , Dykier Katherine C. , Hess Matthias
Published: October 2018

There has been a great interest to identify a microbial marker that can be used to predict feed efficiency of beef cattle. Such a marker, specifically one that would allow an early identification of animals with high feed efficiency for future breeding efforts, would facilitate increasing the profitability of cattle operations and simultaneously render them more sustainable by reducing their methane footprint. The work presented here suggests that Prevotella copri might be an ideal microbial marker for identifying beef cattle with high feed efficiency early in their life span and in the production cycle. Developing more refined quantification techniques that allow correlation of P. copri to feed efficiency of beef cattle that can be applied by lay people in the field holds great promise to improve the economy of cattle operations while simultaneously reducing their environmental impact by mitigating methane production from enteric fermentation.
Zika Virus Subverts Stress Granules to Promote and Restrict Viral Gene Expression
Authors: Bonenfant Gaston , Williams Nina , Netzband Rachel , Schwarz Megan C. , Evans Matthew J. , Pager Cara T.
Published: October 2018

Flaviviruses limit the cell stress response by preventing the formation of stress granules and modulate viral gene expression by subverting different proteins involved in the stress granule pathway. In this study, we investigated the formation of stress granules during Zika virus (ZIKV) infection and the role stress granule proteins play during the viral life cycle. Using immunofluorescence and confocal microscopy, we determined that ZIKV disrupted the formation of arsenite-induced stress granules and changed the subcellular distribution, but not the abundance or integrity, of stress granule proteins. We also investigated the role of different stress granule proteins in ZIKV infection by using target-specific siRNAs to deplete Ataxin2, G3BP1, HuR, TIA-1, TIAR and YB1. Knock-down of TIA-1 and TIAR affected ZIKV protein and RNA levels, but not viral titers. Conversely, depletion of Ataxin2 and YB1 decreased virion production despite having only a small effect on ZIKV protein expression. Notably, however, depletion of G3BP1 and HuR decreased and increased ZIKV gene expression and virion production, respectively. Using an MR766Gaussialuciferase reporter genome together with knockdown and overexpression assays, G3BP1 and HuR were found to modulate ZIKV replication. These data indicate that ZIKV disrupts the formation of stress granules by sequestering stress granule proteins required for replication, where G3BP1 functions to promote ZIKV infection, while HuR exhibits an antiviral effect. The consequence of ZIKV re-localizing and subverting select stress granule proteins might have broader consequences on cellular RNA homeostasis and contribute to cellular gene dysregulation and ZIKV pathogenesis.

Importance

Many viruses inhibit stress granules (SGs). In this study, we observed that ZIKV restricts SG assembly likely by re-localizing and subverting specific SG proteins to modulate ZIKV replication. This ZIKV-SG protein interaction is interesting, as many SG proteins are also known to function in neuronal granules, which are critical in neural development and function. Moreover, dysregulation of different SG proteins in neurons has been shown to play a role in the progression of neurodegenerative diseases. The likely consequences of ZIKV modulating SG assembly and subverting specific SG proteins are alterations to cellular mRNA transcription, splicing, stability, and translation. Such changes in cellular ribostasis could profoundly affect neural development and contribute to the devastating developmental and neurological anomalies observed following intrauterine ZIKV infection. Our study provides new insights into virus-host interactions and the identification of the SG proteins that may contribute to the unusual pathogenesis associated with this re-emerging arbovirus.
Longitudinal plasma metabolomics of aging and sex
Authors: Darst Burcu F. , Koscik Rebecca L. , Hogan Kirk J. , Johnson Sterling C. , Engelman Corinne D.
Published: October 2018

Understanding how metabolites are longitudinally influenced by age and sex could facilitate the identification of metabolomic profiles and trajectories that indicate disease risk. We investigated the metabolomics of age and sex using longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment. Metabolomic profiles were quantified for 2,316 fasting plasma samples among 1,187 participants, each with up to three study visits. Of 1,097 metabolites tested, 608 (55.4%) were associated with age and 680 (62.0%) with sex after correcting for multiple testing. Approximately twice as many metabolites were associated with age in stratified analyses of women versus men, and 63 metabolite trajectories significantly differed by sex, most notably including sphingolipids, which tended to increase in women and decrease in men with age. Using genome-wide genotyping, we also report the heritabilities of metabolites investigated, which ranged dramatically (0.2-99.2%); however, the median heritability of 36.2% suggests that many metabolites are highly influenced by a complex combination of genomic and environmental influences. These findings offer a more profound description of the aging process and may inform many new hypotheses regarding the role metabolites play in healthy and accelerated aging.
Deep Convolutional Network for Animal Sound Classification and Source Attribution using Dual Audio Recordings
Authors: Oikarinen Tuomas , Srinivasan Karthik , Meisner Olivia , Hyman Julia B. , Parmar Shivangi , Desimone Robert , Landman Rogier , Feng Guoping
Published: October 2018

We introduce an end-to-end feedforward convolutional neural network that is able to reliably classify the source and type of animal calls in a noisy environment using two streams of audio data after being trained on a dataset of modest size and imperfect labels. The data consists of audio recordings from captive marmoset monkeys housed in pairs, with several other cages nearby. Our network can classify both the call type and which animal made it with a single pass through a single network using raw spectrogram images as input. The network vastly increases data analysis capacity for researchers interested in studying marmoset vocalizations, and allows data collection in the home cage, in group housed animals.
A histidine kinase gene is required for large radius root tip circumnutation and surface exploration in rice
Authors: Lehner Kevin R. , Taylor Isaiah , McCaskey Erin N. , Jain Rashmi , Ronald Pamela C. , Goldman Daniel I. , Benfey Philip N.
Published: October 2018

The intricate growth patterns that accompany plant organ elongation have long intrigued biologists 1. Circumnutation refers to the circular or elliptical growth of the tip of a plant organ around a central axis. While the utility of circumnutation for climbing plants is clear, its function in roots is less obvious. Additionally, the genetic requirements for root circumnutation are not known. Here we show that mutations in a gene encoding a histidine kinase abolish large radius root tip circumnutation in rice. Using a gel-based imaging system and a whole genome sequenced mutant population, we identified three different mutant alleles of the gene OsHK1 that exhibit increased seedling root depth. Time-lapse imaging indicated that this phenotype is likely due to a lack of large radius root tip circumnutation in OsHK1 mutants. Treatment of mutant roots with the plant hormone zeatin rescues circumnutation, indicating that OsHK1 functions in a cytokinin-related signaling pathway. We found that OsHK1 mutants are impaired in their ability to explore flat surfaces, suggesting that circumnutation facilitates root exploration at the interface of compacted soil horizons.