bluuebunny/crossref_metadata_2025 huggingface dataset:
Medication Adherence Among Patients With Chronic Hepatitis Receiving Antiviral Treatment
Authors: Go Hirofumi , Tanaka Makoto , Yamamoto-Mitani Noriko , Suzuki Miho , Kawakami Aki , Masaki Naohiko , Shimada Megumi
Published: April 2019

This study aimed to evaluate medication adherence and associated factors among patients with chronic viral hepatitis. A cross-sectional questionnaire survey was conducted in 171 outpatients receiving antiviral treatment of chronic viral hepatitis at 6 national/regional liver disease treatment centers in Japan. Medication adherence was calculated as the subject-reported number of antiviral tablets taken in the past 2 weeks compared with the prescribed number of tablets. Subjects were divided according to 100% adherence or nonadherence. The impact of items pertaining to everyday experiences and perceptions regarding medication adherence were examined. Factors associated with medication adherence were identified via multiple logistic regression. The mean medication adherence rate was 95.8% ± 9.5% (range = 0%–100%), although a smaller proportion (95 subjects; 55.6%) was 100% adherent. Multiple logistic regression indicated a greater “lack of understanding of need for medication” (1 point: odds ratio (OR) = 1.51, 95% confidence interval (CI) [1.30, 1.76], p ≤ .01) and greater “restriction in life due to medication” (1 point: OR = 1.26, 95% CI [1.03, 1.54], p = 0.03) as associated with nonadherence. In conclusion, to improve medication adherence, healthcare professionals should improve patients' understanding of the need for medication and minimization of life restrictions.
Eliminating Institutional Barriers to Career Advancement for Diverse Faculty in Academic Surgery
Authors: Newman Erika A. , Waljee Jennifer , Dimick Justin B. , Mulholland Michael W.
Published: April 2019

There is critical need to address achievement barriers in Academic Medicine. Although opportunities for professional development of women and underrepresented minority physician scientists are growing, academic promotion rates remain historically low. Moreover, underrepresented groups are not likely to advance to decanal and leadership positions. To eliminate institutional barriers to achievement for diverse faculty, strategies to strengthen environment, recruitment, professional development, and leadership were implemented. This multifaceted approach is adaptable to Academic Surgery universally and we wish to share early progress.
Outcome of 1000 Patients With Gastrointestinal Stromal Tumor (GIST) Treated by Surgery in the Pre- and Post-imatinib Eras
Authors: Cavnar Michael J. , Seier Kenneth , Curtin Christina , Balachandran Vinod P. , Coit Daniel G. , Yoon Sam S. , Crago Aimee M. , Strong Vivian E. , Tap William D. , Gönen Mithat , Antonescu Cristina R. , Brennan Murray F. , Singer Sam , DeMatteo Ronald P.
Published: April 2019

Objective:

To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors.

Background:

Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined.

Methods:

We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS).

Results:

OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00–7.40, P < 0.0001) and OS (HR 3.37, 95% CI 1.60–7.13, P = 0.001)].

Conclusions:

Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.
Impact of Oral Immunonutrition on Postoperative Morbidity in Digestive Oncologic Surgery
Authors: Challine Alexandre , Rives-Lange Claire , Danoussou Divya , Katsahian Sandrine , Ait Boudaoud Amel , Gaujoux Sébastien , Dousset Bertrand , Carette Claire , Lazzati Andrea , Czernichow Sébastien
Published: April 2019

Objective:

The objective of the present study was to assess the effect of preoperative immunonutrition on a nationwide scale.

Background:

According to international guidelines, immunonutrition should be prescribed before major oncologic digestive surgery to decrease postoperative morbidity. Nevertheless, this practice remains controversial.

Methods:

We used a prospective national health database named “Echantillon généraliste des Bénéficiaires.” Patients were selected with ICD10 codes of cancer and digestive surgery procedures from 2012 to 2016. Two groups were identified: with reimbursement of immunonutrition 45 days before surgery (IN-group) or not (no-IN-group). Primary outcome was 90-day severe morbidity. Secondary outcomes were postoperative length of stay (LOS) and overall survival. Logistic regression and survival analysis adjusted with IPW method were performed.

Results:

One thousand seven hundred seventy-one patients were included. The proportion of different cancers was as follows: 72% patients were included in the colorectal group, 14% in the hepato-pancreato-biliary group, and 12% in the upper gastrointestinal group. Patients from the IN-group (n = 606, 34%) were younger (67.1 ± 11.8 vs 69.2 ± 12.2 years, P < 0.001), with increased use of other oral nutritional supplements (49.5% vs 31.8%, P < 0.001) and had more digestive anastomoses (89.4% vs 83.0%, P < 0.001). There was no significant difference between the 2 groups for 90-day severe morbidity [odds ratio (OR): 0.91, 95% confidence interval (95% CI): 0.73–1.14] or in survival (hazard ratio: 0.89, 95% CI: 0.73–1.08). LOS were shorter in the IN-group [−1.26 days, 95% CI: −2.40 to −0.10)].

Conclusion:

The preoperative use of immunonutrition before major oncologic digestive surgery was not associated with any significant difference in morbidity or mortality. However, the LOS was significantly shorter in the IN-group.
A Study on Radial Margin Status in Resected Perihilar Cholangiocarcinoma
Authors: Shinohara Kentaro , Ebata Tomoki , Shimoyama Yoshie , Mizuno Takashi , Yokoyama Yukihiro , Yamaguchi Junpei , Onoe Shunsuke , Watanabe Nobuyuki , Nagino Masato
Published: April 2019

Objective:

To investigate radial margin (RM) status in resected perihilar cholangiocarcinoma (PHCC) and to evaluate the incidence of positive RM and its effect on survival.

Background:

Although numerous studies have reported on ductal margin (DM) status in resected PHCC, no studies have addressed RM status.

Methods:

Patients who underwent hepatectomy for PHCC between 2001 and 2014 were retrospectively reviewed. After formalin fixation, resected specimens were serially sectioned at 5-mm intervals. All serial sections were color-copied, and RMs and DMs were identified and indicated on the color copies.

Results:

Among 478 patients, 85 (17.8%) had positive surgical margins (R1 resection); of the 85 patients, 37 had positive RM alone, 33 had positive DM alone, and the remaining 15 had both positive RM and positive DM. Overall, 52 (61.2%) patients had positive RM. The sites of positive RM included the liver transection plane (n = 20) and the dissection plane in the hepatoduodenal ligament (n = 32). RM positivity on the liver transection plane was higher in left hepatectomy than in other hepatectomies (9.2% vs 1.9%, P < 0.001). RM positivity in the hepatoduodenal ligament was higher in left-sided hepatectomy than in right-sided hepatectomy (8.7% vs 3.6%, P = 0.031). The survival of the patients with positive RM was poorer than that of R0 patients (MST 2.1 vs 4.9 yrs, P < 0.001) and was similar to that of patients with positive DM. Multivariate analysis identified positive RM as one of the independent prognostic factors.

Conclusions:

Positive RM was the most common cause of R1 resection of PHCC and had similarly negative effects on survival as positive DM. Meticulous handling of the resected specimen is important to accurately evaluate RM status together with DM status.
Yoga for Women With Urgency Urinary Incontinence: A Pilot Study
Authors: Tenfelde Sandi , Tell Dina , Garfield Lindsey , Mathews Herbert , Janusek Linda
Published: April 2019

Objectives

The objective of this study was to evaluate the feasibility of a gentle yoga program for women with urgency urinary incontinence (UUI). Also, these preliminary data can evaluate if yoga improves symptom burden, quality of life, and inflammatory biomarkers for women with UUI.

Methods

This prospective nonrandomized single-arm pilot study evaluated the effectiveness of a twice-weekly, 8-week gentle yoga intervention to reduce UUI symptom burden. Changes in symptom burden were measured using the Pelvic Floor Distress Inventory 20. Secondary measures included quality of life, depressive symptoms, sleep, stress, anxiety, and inflammatory biomarkers. Outcomes were evaluated with paired t testing.

Results

Twelve women completed the yoga intervention with no adverse outcomes noted. Urgency symptom burden was significantly improved after the intervention (P = 0.01), and women reported an increase in quality of life (P = 0.04) after the yoga intervention. Following the yoga intervention, the majority of women reported symptoms as “much better” (n = 4 [33%]) and “a little better” (n = 5 [42%]), with 3 women (25%) reporting “no change.” Women also reported significant reduction in depressive symptoms (P = 0.03) and better quality of sleep (P = 0.03). No significant changes were found in anxiety or stress perception. Plasma levels of the inflammatory biomarker tumor necrosis factor α were reduced after yoga intervention (P = 0.009); however, no significant postyoga changes were found for interleukin 6 or C-reactive protein.

Conclusions

This study provides preliminary evidence that yoga is a feasible complementary therapy that reduces incontinence symptom burden, along with improving quality of life, depressive symptoms, and sleep quality. Additionally, yoga may lower inflammatory biomarkers associated with incontinence.
Normothermic Machine Perfusion Enhances Intraoperative Hepatocellular Synthetic Capacity: A Propensity Score-matched Analysis
Authors: Ionescu Mihnea-Ioan , Tillakaratne Suchintha , Hodson James , Gunson Bridget , Nasralla David , Pinter Carvalheiro da Silva Boteon Amanda , Sermon Kate , Mergental Hynek , Isaac John R. , Roberts John K. , Muiesan Paolo , Friend Peter , Mirza Darius F. , Bennett Davinia , Perera M. Thamara P.R.
Published: April 2019

Background.

Normothermic machine perfusion (NMP) of liver grafts is increasingly being incorporated in clinical practice. Current evidence has shown NMP plays a role in reconditioning the synthetic and energy capabilities of grafts. Intraoperative coagulation profile is a surrogate of graft quality and preservation status; however, to date this aspect has not been documented.

Methods.

The liver transplantation recipients who received NMP liver grafts in the QEHB between 2013 and 2016 were compared in terms of intraoperative thromboelastography characteristics (R time, K time, α-angle, maximum amplitude, G value, and LY30) to a propensity score-matched control group, where the grafts were preserved by traditional static cold storage (SCS).

Results.

After propensity matching, none of the thromboelastography characteristics were found to differ significantly between the 72 pairs of SCS and NMP organs when measured preimplantation. However, postimplantation, NMP organs had significantly shorter K time (median: 2.8 vs 3.6 min, P = 0.010) and R + K time (11.4 vs 13.7 min, P = 0.016), as well as significantly larger α-angle (55.9° vs 44.8°, P = 0.002), maximum amplitude (53.5 vs 49.6 mm, P = 0.044), and G values (5.8 vs 4.9k dynes/cm2, P = 0.043) than SCS organs. Hyperfibrinolysis after implantation was also mitigated by NMP, with fewer patients requiring aggressive factor correction during surgery (LY30 = 0, NMP vs SCS: 83% vs 60%, P = 0.004). Consequently, NMP organs required significantly fewer platelet units to be transfused during the transplant procedure (median: 0 vs 5, P = 0.001).

Conclusions.

In this study, we have shown that NMP liver grafts return better coagulation profiles intraoperatively, which could be attributed to the preservation of liver grafts under physiological conditions.
NRF2 drug repurposing using a question-answer artificial intelligence system
Authors: Mickael Michel-Edwar , Pajares Marta , Enache Ioana , Manda Gina , Cuadrado Antonio
Published: April 2019

Drug repurposing represents an innovative approach to reduce the drug development timeline. Text mining using artificial intelligence methods offers great potential in the context of drug repurposing. Here, we present a question-answer artificial intelligence (QAAI) system that is capable of repurposing drug compounds. Our system employs a Google semantic AI universal encoder to compute the sentence embedding of an imposed text question in relation to publications stored in our RedBrain JSON database. Sentences similarity is calculated using a sorting function to identify drug compounds. We demonstrate our system’s ability to predict new indications for already existing drugs. Activation of the NRF2 pathway seems critical for enhancing several diseases prognosis. We experimentally validated the prediction for the lipoxygenase inhibitor drug zileuton as a modulator of the NRF2 pathway in vitro, with potential applications to reduce macrophage M1 phenotype and ROS production. This novel computational method provides a new approach to reposition of known drugs in order to treat neurodegenerative diseases. Github for the database and the code can be downloaded fromhttps://gist.github.com/micheledw/5a165b44345d45105d715340b88c756b
Trichoplein controls endothelial cell function by regulating autophagy
Authors: Martello Andrea , Lauriola Angela , Mellis David , Parish Elisa , Dawson John C , Imrie Lisa , Vidmar Martina , Gammoh Noor , Mitic Tijana , Brittan Mairi , Mills Nicholas , Carragher Neil O , D’Arca Domenico , Caporali Andrea
Published: April 2019

Autophagy is an essential cellular quality control process that emerged critical for vascular homeostasis. Here we describe, the role for Trichoplein (TCHP) protein in linking autophagy with endothelial cells (ECs) function. The depletion of TCHP in ECs impairs migration and sprouting. TCHP directly binds PCM1, to regulate degradation of GABARAP, thus leading to a defective autophagy. Mechanistically, TCHP is indispensable for autophagosome maturation and its depletion resulted in the accumulation of SQSTM1/p62 (p62) and unfolded protein aggregates in ECs. The latter process is coupled to TCHP-mediated NF-kB activation. Of note, low levels of TCHP and high p62 levels were detected in primary ECs from patients with coronary artery disease. In addition, Tchp knock-out mice showed accumulation of p62 in the heart and cardiac vessels and reduced cardiac vascularization. Here, we reveal an autophagy-mediated mechanism for TCHP down-regulation, which poses a plausible target for regulation of endothelial function.
Genomic analysis reveals selection signatures of Yucatan miniature pig on its X chromosome during domestication
Authors: Zhang Wei , Wang Yuanlang , Yang Min , Wu Xudong , Zhang Xiaodong , Ding Yueyun , Yin Zongjun
Published: April 2019

Yucatan miniature pig (YMP), a naturally small breed, has been domesticated in the hot and arid Yucatan Peninsula for a long time. However, its selection signatures on the X chromosome remain poorly understood. In this study, we focused on elucidating the selection signatures of YMP on the X chromosome during its domestication and breeding, using the whole-genome sequencing data. We performed population admixture analyses to determine its genetic relationships with other domesticated breeds and wild boars. Subsequently, we used two approaches, the fixation index (Fst) and π ratios, to identify the selection signatures with 100 kb windows sliding in 10 kb steps. As a result, we found that the ectodysplasin A (EDA) gene was related with hypoplasia or absence of hair and sweat glands. This could uncover the relative lack of odor in YMP and the presence of hypoplasia or absence of hair in pigs. Furthermore, we found several genes under selection in other animals. A bioinformatics analysis of the genes in selection regions showed that they were associated with growth, lipid metabolism, reproduction, and immune system. Our findings will lead to a better understanding of the unique genetic and phenotypic characteristics of YMP and offer a plausible method for their utilization as an animal model for hair and odor disease research.
Clinical long-read sequencing of the human mitochondrial genome for mitochondrial disease diagnostics
Authors: Wood Elizabeth , Parker Matthew D , Dunning Mark J , Hesketh Sirisha , Wang Dennis , Pink Ryan , Fratter Carl
Published: April 2019

Purpose

Long-read, third generation, sequencing technologies have the potential to improve current state of the art diagnostic strategies. In order to determine if long-read sequencing technologies are suitable for the diagnosis of mitochondrial disorders due to mitochondrial DNA (mtDNA) variants, particularly large deletions, we compared the performance of Oxford Nanopore Technologies (ONT) MinION to current diagnostic methods.

Methods

We sequenced mtDNA from nine patients with mtDNA deletion disorders and three normal controls with both ONT MinION and Illumina MiSeq. We applied a computational pipeline to estimate the positions of mtDNA deletions in patients, and subsequently validated the breakpoints using Sanger sequencing.

Results

We were able to detect mtDNA deletions with a MinION workflow, successfully calling the disease causing event in all cases. Sequencing coverage was in most cases significantly more (p=0.03, Wilcoxon test) uniform with MinION than with MiSeq and subsequent correction of MinION reads improved breakpoint accuracy and reduced false positives. Although heteroplasmic single nucleotide variants are detectable, the high number of false positives and false negatives precludes their use in diagnostics at this time.

Conclusion

The MinION is becoming an increasingly attractive diagnostic tool due to the reducing cost, increasing accuracy, and the speed at which data can be obtained.
Altered dynamics may drift pathological fibrillization in membraneless organelles
Authors: Tüű-Szabó B. , Hoffka G. , Duro N. , Koczy L. , Fuxreiter M.
Published: April 2019

Protein phase transition can generate non-membrane bound cellular compartments, which can convert from liquid-like to solid-like states. While the molecular driving forces of phase separation have been largely understood, much less is known about the mechanisms of material-state conversion. We apply a recently developed algorithm to describe the weak interaction network of multivalent motifs, and simulate the effect of pathological mutations. We demonstrate that linker dynamics is critical to the material-state of biomolecular condensates. We show that linker flexibility/mobility is a major regulator of the weak, heterogeneous meshwork of multivalent motifs, which promotes phase transition and maintains a liquid-like state. Decreasing linker dynamics increases the propensity of amyloid-like fragments via hampering the motif-exchange and reorganization of the weak interaction network. In contrast, increasing linker mobility may compensate rigidifying mutations, suggesting that the meshwork of weak, variable interactions may provide a rescue mechanism from aggregation. Motif affinity, on the other hand, has a moderate impact on fibrillization. Here we demonstrate that the fuzzy framework provides an efficient approach to handle the intricate organization of membraneless organelles, and could also be applicable to screen for pathological effects of mutations.
Joint RElaxation-Diffusion Imaging Moments (REDIM) to probe neurite microstructure
Authors: Ning Lipeng , Gagoski Borjan , Szczepankiewicz Filip , Westin Carl-Fredrik , Rathi Yogesh
Published: April 2019

Joint relaxation-diffusion measurements can provide new insight about the tissue microstructural properties. Most recent methods have focused on inverting the Laplace transform to recover the joint distribution of relaxation-diffusion. However, as is well-known, this problem is notoriously ill-posed and numerically unstable. In this work, we address this issue by directly computing the joint moments of transverse relaxation rate and diffusivity, which can be robustly estimated. To zoom into different parts of the joint distribution, we further enhance our method by applying multiplicative filters to the joint probability density function of relaxation and diffusion and compute the corresponding moments. We propose an approach to use these moments to compute several novel scalar indices to characterize specific properties of the underlying tissue microstructure. Furthermore, for the first time, we propose an algorithm to estimate diffusion signals that are independent of echo time based on the moments of the marginal probability density function of diffusion. We demonstrate its utility in extracting tissue information not contaminated with multiple intra-voxel relaxation rates. We compare the performance of four types of filters that zoom into tissue components with different relaxation and diffusion properties and demonstrate it on an in-vivo human dataset. Experimental results show that these filters are able to characterize heterogeneous tissue microstructure. Moreover, the filtered diffusion signals are also able to distinguish fiber bundles with similar orientations but different relaxation rates. The proposed method thus allows to characterize the neural microstructure information in a robust and unique manner not possible using existing techniques.
“Stretch-Growth” of Motor Axons in Custom Mechanobioreactors to Generate Long-Projecting Axonal and Axonal-Myocyte Constructs
Authors: Katiyar Kritika S. , Struzyna Laura A. , Das Suradip , Cullen D. Kacy
Published: April 2019

The central feature of peripheral motor axons is their remarkable lengths as they project from a motor neuron residing in the spinal cord to an often-distant target muscle. However, to date in vitro models have not replicated this central feature owing to challenges in generating motor axon tracts beyond a few millimeters in length. To address this, we have developed a novel combination of micro-tissue engineering and mechanically assisted growth techniques to create long-projecting centimeter-scale motor axon tracts. Here, primary motor neurons were isolated from the spinal cords of rats and induced to form engineered micro-spheres via forced aggregation in custom micro-wells. This three-dimensional micro-tissue yielded healthy motor neurons projecting dense, fasciculated axonal tracts. Within our custom-built mechanobioreactors, motor neuron culture conditions, neuronal/axonal architecture, and mechanical growth conditions were systematically optimized to generate parameters for robust and efficient “stretch-growth” of motor axons. We found that axons projecting from motor neuron aggregates were able to respond to axon displacement rates at least 10 times greater than that tolerated by axons projecting from dissociated motor neurons. The growth and structural characteristics of these stretch-grown motor axons were compared to benchmark stretch-grown axons from sensory dorsal root ganglion neurons, revealing similar axon densities yet increased motor axon fasciculation. Finally, motor axons were integrated with myocytes and then stretch-grown to create novel long-projecting axonal-myocyte constructs that better recreate characteristic dimensions of native nerve-muscle anatomy. This is the first demonstration of mechanical elongation of spinal cord motor axons and may have applications as anatomically inspired in vitro testbeds or as tissue engineered “living scaffolds” for targeted axon tract reconstruction following nervous system injury or disease.

Significance Statement

We have developed novel axon tracts of unprecedented lengths spanning either two discrete populations of neurons or a population of neurons and skeletal myocytes. This is the first demonstration of “stretch-grown” motor axons that recapitulate the structure of spinal motor neurons in vivo by projecting long axons from a pool of motor neurons to distant targets, and may have applications as anatomically inspired in vitro test beds to study mechanisms of axon growth, development, and neuromuscular function in anatomically accurate axo-myo constructs; as well as serve as “living scaffolds” in vivo for targeted axon tract reconstruction following nervous system trauma.
Coupling multiplex pre-amplification and droplet digital PCR for longitudinal monitoring ofESR1andPIK3CAmutations from plasma cell-free DNA
Authors: Yao Huilan , Wu Grant , Das Subhasree , MacKenzie Crystal , Gao Hua , Rimkunas Victoria , Zhang Zhaojie , Ferro Stephanie , Roden Amy , Korpal Manav , Schindler Joanne , Smith Peter G. , Yu Lihua , Zhu Ping , Kumar Pavan
Published: April 2019

Here we report on the development of a sensitive and cost-effective method to longitudinally trackESR1andPIK3CAmutations from cfDNA in patients with metastatic breast cancer (MBC) using a streamlined and de-centralized workflow. Hotspot mutations inESR1have been shown to cause resistance to aromatase inhibitor–based and anti-estrogenic therapies, whilePIK3CAmutations have high prevalence in MBC. As a result, their utility as circulating biomarkers to predict or monitor response in the clinical development of investigational compounds has been the focus of many studies. Six regions inESR1andPIK3CAgenes containing 20 hotspot mutations were pre-amplified, followed by optimized singleplex ddPCR assays to detect allele frequencies of individual mutations. Without pre-amplification, the limit of detection (LOD) and limit of linearity (LOL) of individual ddPCR assays were at 0.05-0.1% and 0.25% level, respectively. With pre-amplification, the LOD and LOL were slightly elevated at 0.1-0.25% and 0.25-0.5% levels, respectively. High concordance was achieved to the BEAMing assay (Sysmex Inostics) for mutation positive assays (r=0.98, P<0.0001). In conclusion, coupling pre-amplification and ddPCR assays allowed us for the detection of up to 20 hot spot mutations inESR1andPIK3CAwith high sensitivity and reproducibility.
Multiplexed129Xe HyperCEST MRI detection of genetically-reconstituted bacterial protein nanoparticles in human cancer cells
Authors: Mizushima Ryota , Inoue Kanako , Fujiwara Hideaki , Iwane Atsuko H. , Watanabe Tomonobu M. , Kimura Atsuomi
Published: April 2019

Gas vesicle nanoparticles (GVs) are gas-containing protein assemblies expressed in bacteria and archaea. Recently, GVs have gained considerable attention for biotechnological applications as genetically-encodable contrast agents for MRI and ultrasonography. However, at present, the practical use of GVs is hampered by a lack of robust methodology for their induction into mammalian cells. Here, we demonstrate the genetic reconstitution of protein nanoparticles with characteristic bicone structures similar to natural GVs in a human breast cancer cell line KPL-4, and genetic control of their size and shape through expression of reduced sets of humanized gas vesicle genes cloned into Tol2 transposon vectors, referencing the natural gas vesicle gene clusters of the cyanobacteriaplanktothrix rubescens/agardhii.We then report the utility of these nanoparticles as multiplexed, sensitive and genetically-encoded contrast agents for hyperpolarized xenon chemical exchange saturation transfer (HyperCEST) MRI.
Anticipatory distractor suppression elicited by statistical regularities in visual search
Authors: Wang Benchi , van Driel Joram , Ort Eduard , Theeuwes Jan
Published: April 2019

Salient yet irrelevant objects often capture our attention and interfere with our daily tasks. Distraction by salient objects can be reduced by suppressing the location where they are likely to appear. The question we addressed here was whether suppression of frequent distractors is already implemented beforehand, in anticipation of the stimulus. Using electroencephalography (EEG), we recorded cortical activity of human participants searching for a target while ignoring a salient distractor. The distractor was presented more often at one location than at any other location. We found reduced capture for distractors at frequent locations, indicating that participants learned to avoid distraction. Critically, we found evidence for proactive suppression as already prior to display onset, there was enhanced power in parieto-occipital alpha oscillations contralateral to the frequent distractor location – a signal known to occur in anticipation of irrelevant information. Locked to display onset, event-related potentials analysis showed a distractor-suppression-related PD component for this location. Importantly, this PD was found regardless of whether distracting information was presented at the frequent location. In addition, there was an early PD component representing an early attentional index of the frequent distractor location. Our results are show anticipatory (proactive) suppression of frequent distractor locations in visual search already starting prior to display onset.
Gallery Game: Smartphone-based Assessment of Long-Term Memory in Adults at Risk of Alzheimer’s Disease
Authors: Lancaster Claire , Koychev Ivan , Blane Jasmine , Chinner Amy , Chatham Christopher , Taylor Kirsten , Hinds Chris
Published: April 2019

Gallery Game, deployed within the Mezurio smartphone app, targets the processes of episodic memory first vulnerable to neurofibrillary tau-related degeneration in Alzheimer’s Disease, prioritising both perirhinal and entorhinal cortex/hippocampal demands. Thirty-five healthy adults (aged 40-59 years), biased towards those at elevated familial risk of dementia, completed daily Gallery Game tasks for a month. Assessments consisted of cross-modal paired-associate learning, with subsequent tests of recognition and recall following delays ranging from one to 13 days. There was a non-linear decline in memory retention with increasing delays between learning and test, with significant forgetting first reported following delays of three and five days for paired-associate recall and recognition respectively, supporting the need for ecologically valid measures of longer-term memory. Gallery Game outcomes correlated as expected with established neuropsychological memory assessments, confirming the validity of this digital assessment of episodic memory. In addition, there was preliminary support for utilising the perirhinal-dependent pattern of semantic errors during object recognition as a marker of early impairment, justifying ongoing validation against traditional biomarkers of Alzheimer’s disease.
Binning unassembled short reads based on k-mer covariance using sparse coding
Authors: Kyrgyzov Olexiy , Prost Vincent , Gazut Stéphane , Farcy Bruno , Brüls Thomas
Published: April 2019

Sequence binning techniques enable the recovery of a growing number of genomes from complex microbial metagenomes and typically require prior metagenome assembly, incurring the computational cost and drawbacks of the latter, e.g. biases against low-abundance genomes and inability to conveniently assemble multi-terabyte datasets.

We present here a scalable pre-assembly binning scheme (i.e. operating on unassembled short reads) enabling latent genomes recovery by leveraging sparse dictionary learning and elastic-net regularization, and its use to recover hundreds of metagenome-assembled genomes, including very low-abundance genomes, from a joint analysis of microbiomes from the LifeLines-Deep population cohort (n=1135, > 1010 reads).

We showed that sparse coding techniques can be leveraged to carry out read-level binning at large scale, and that despite lower genome reconstruction yields compared to assembly-based approaches, bin-first strategies can complement the more widely used assembly-first protocols by targeting distinct genome segregation profiles. Read enrichment levels across six orders of magnitude in relative abundance were observed, indicating that the method is able to recover genomes consistently segregating at low levels.
The emergence of sequence-dependent structural motifs in stretched, torsionally constrained DNA
Authors: Shepherd Jack W , Greenall R J , Probert M I J , Noy Agnes , Leake Mark C.
Published: April 2019

The double-helical structure of DNA results from canonical base pairing and stacking interactions. However, variations from steady-state conformations result from mechanical perturbations in cells. These different topologies have physiological relevance but their dependence on sequence remains unclear. Here, we use molecular dynamics simulations to show that sequence differences result in markedly different structural motifs upon physiological twisting and stretching. We simulated overextension on four different sequences of DNA ((AA)12, (AT)12, (GG)12and (GC)12) with supercoiling densities within the physiological range. We found that DNA denatures in the majority of stretching simulations, surprisingly including those with overtwisted DNA. GC-rich sequences were observed to be more stable than AT-rich, with the specific response dependent on base pair ordering. Furthermore, we found that (AT)12forms stable periodic structures with non-canonical hydrogen bonds in some regions and non-canonical stacking in others, whereas (GC)12forms a stacking motif of four base pairs independent of supercoiling density. Our results demonstrate that 20-30% DNA extension is sufficient for breaking B-DNA around and significantly above cellular supercoiling, and that the DNA sequence is crucial for understanding structural changes under mechanical stress. Our findings have important implications for the activities of protein machinery interacting with DNA in all cells.
An inactivation switch enables rhythms in aNeurosporaclock model
Authors: Upadhyay Abhishek , Brunner Michael , Herzel Hanspeter
Published: April 2019

An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungusNeurospora crassais a well established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock ofNeurosporais composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedbacks among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 hrs. Our model reveals a switch between WC1 induced transcription and FFC assisted inactivation of WC1. Using the new model we also study possible mechanisms of glucose compensation. A fairly simple model with just 3 non-linearities helps to elucidate clock dynamics revealing a mechanism of rhythms production. The model can further be utilized to study entrainment and temperature compensation.
The role of mesotocin on social bonding in pinyon jays
Authors: Duque Juan F. , Rasmussen Tanner , Rodriguez Anna , Stevens Jeffrey R.
Published: April 2019

The neuropeptide oxytocin influences mammalian social bonding by facilitating the building and maintenance of parental, sexual, and same-sex social relationships. However, we do not know whether the function of the avian homologue mesotocin is evolutionarily conserved across birds. While it does influence avian prosocial behavior, mesotocin’s role in avian social bonding remains unclear. Here, we investigated whether mesotocin regulates the formation and maintenance of same-sex social bonding in pinyon jays (Gymnorhinus cyanocephalus), a member of the crow family. We formed squads of four individually housed birds. In the first, ‘pair-formation’ phase of the experiment, we repeatedly placed pairs of birds from within the squad together in a cage for short periods of time. Prior to entering the cage, we intranasally administered one of three hormone solutions to both members of the pair: mesotocin, oxytocin antagonist, or saline. Pairs received repeated sessions with administration of the same hormone. In the second, ‘pair-maintenance’ phase of the experiment, all four members of the squad were placed together in a large cage, and no hormones were administered. For both phases, we measured the physical proximity between pairs as our proxy for social bonding. We found that, compared to saline, administering mesotocin or oxytocin antagonist did not result in different proximities in either the pair-formation or pair-maintenance phase of the experiment. Therefore, at the dosages and time frames used here, exogenously introduced mesotocin did not influence same-sex social bond formation or maintenance. Like oxytocin in mammals, mesotocin regulates avian prosocial behavior; however, unlike oxytocin, we do not have evidence that mesotocin regulates social bonds in birds.
Novel characterization of peptidergic release from prefrontal cortical somatostatin neurons
Authors: Dao Nigel , Brockway Dakota F. , Crowley Nicole A.
Published: April 2019

Somatostatin is a neuropeptide thought to play a role in a variety of neuropsychiatric disorders, and is important for healthy aging and behavioral resiliency. Conditions governing somatostatin peptidergic release are not well-defined. Using a combination of optogenetic, transgenic, and biochemical approaches, we demonstrate an assay for the induction and inhibition of somatostatin in acute brain slices.
The HAC1 Histone Acetyltransferase Promotes Leaf Senescence via Regulation of ERF022
Authors: Hinckley Will E. , Keymanesh Keykhosrow , Cordova Jaime A. , Brusslan Judy A.
Published: April 2019

Nutrient remobilization during leaf senescence nourishes the growing plant. Understanding the regulation of this process is essential for reducing our dependence on nitrogen fertilizers and increasing agricultural sustainability. Our lab is interested in chromatin changes that accompany the transition to leaf senescence. Previously, darker green leaves were reported for Arabidopsis thaliana hac1 mutants, defective in a gene encoding a histone acetyltransferase in the CREB-binding protein family. Here, we show that two Arabidopsis hac1 alleles display delayed age-related developmental senescence, but have normal dark-induced senescence. Using a combination of ChIP-seq for H3K9ac and RNA-seq for gene expression, we identified 44 potential HAC1 targets during age-related developmental senescence. Genetic analysis demonstrated that one of these potential targets, ERF022, is a positive regulator of leaf senescence. ERF022 is regulated additively by HAC1 and MED25, suggesting MED25 recruits HAC1 to the ERF022 promoter to increase its expression in older leaves.
Trans-synaptic Fish-lips Signaling Prevents Misconnections between Non-synaptic Partner Olfactory Neurons
Authors: Xie Qijing , Wu Bing , Li Jiefu , Li Hongjie , Luginbuhl David J , Xu Chuanyun , Wang Xin , Luo Liqun
Published: April 2019

Our understanding of the mechanisms of neural circuit assembly is far from complete. Identification of new wiring molecules with novel mechanisms of action will provide new insights into how complex and heterogeneous neural circuits assemble during development. Here, we performed an RNAi screen for cell-surface molecules and identified the leucine-rich-repeat containing transmembrane protein, Fish-lips (Fili), as a novel wiring molecule in the assembly of theDrosophilaolfactory circuit. Fili contributes to the precise targeting of both olfactory receptor neuron (ORN) axons as well as projection neuron (PN) dendrites. Cell-type-specific expression and genetic analyses suggest that Fili sends a trans-synaptic repulsive signal to neurites of non-partner classes that prevent their targeting to inappropriate glomeruli in the antennal lobe.

Significance Statement

In the fruit fly olfactory system, 50 classes of olfactory receptor neurons (ORNs) make precise synaptic connections with 50 classes of corresponding projection neurons (PNs). Identification of wiring molecules in this circuit can provide insight into understanding neural circuit assembly. This paper reports the role of a transmembrane protein, Fish-lips (Fili), in forming specific connections in this circuit. We found that some ORN axons are repelled by Fili, which is present on dendrites of non-matching PN class, preventing them from targeting inappropriate glomeruli. Similarly, some PN dendrites are repelled by Fili expressed by non-matching ORN class for their correct targeting. Together, these results suggest that Fili mediates repulsion between axons and dendrites of non-synaptic partners to ensure precise wiring patterns.
Retrieval of whole human genome clinical variant information through search motors
Authors: Yin Li , di Iulio Julia , Lelong Sebastien , Wu Chunlei , Telenti Amalio
Published: April 2019

The interpretation of variation in the human genome constitutes one of the most pressing challenges in biomedicine. There are many academic and proprietary resources that provide annotation, interpretation, scoring and knowledge of genetic variants under multiple access modalities. For these resources, information is available through portals, wikis, APIs, curated content and databases, and pipelines. Here we explore the use of search motors to provide facilitated access to the main sources of information that are used by clinical geneticists and researchers. We also support the browsing experience with natural language processing and automated summaries of available information. The resulting tool, ai-OMNI.com, is intrinsically flexible, expandable and intuitive, thus providing a different experience for querying the human genome for the consequences of variation.
Decoding neuronal diversity by single-cell Convert-seq
Authors: Luginbühl Joachim , Kouno Tsukasa , Nakano Rei , Chater Thomas E , Sivaraman Divya M , Kishima Mami , Roudnicky Filip , Carninci Piero , Plessy Charles , Shin Jay W
Published: April 2019

The conversion of cell fates is controlled by hierarchical gene regulatory networks (GRNs) that induce remarkable alterations in cellular and transcriptome states. The identification of key regulators within these networks from myriad of candidate genes, however, poses a major research challenge. Here we present Convert-seq, combining single-cell RNA sequencing (scRNA-seq) and pooled ectopic gene expression with a new strategy to discriminate sequencing reads derived from exogenous and endogenous transcripts. We demonstrate Convert-seq by associating hundreds of single cells during reprogramming of human fibroblasts to induced neurons (iN) with exogenous and endogenous transcriptional signatures. Convert-seq identified GRNs modulating the emergence of developmental trajectories and predicted combinatorial activation of exogenous transcription factors controlling iN subtype specification. Functional validation of iN subtypes generated by novel combinations of exogenous transcription factors establish Convert-seq as a broadly applicable workflow to rapidly identify key transcription factors and GRNs orchestrating the reprogramming of virtually any cell type.
Cognitive Improvements after Intermittent Deep Brain Stimulation of the Nucleus Basalis of Meynert in a Transgenic Rat Model for Alzheimer’s disease; a Preliminary Approach
Authors: Koulousakis Philippos , den Hove Daniel van , Visser-Vandewalle Veerle , Sesia Thibaut
Published: April 2019

Background

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has shown to have promising results in a pilot study with patients suffering from Alzheimer’s disease (AD). A recent study in aged monkeys shows a novel intermittent stimulation pattern to have superior cognitive benefits over continuous paradigms.

Objective/Hypothesis

We aimed at comparing the cognitive effects elicited by intermittent and continuous NBM stimulation paradigms in an animal model for AD (TgF344-AD rat line; TG), i.e. rats expressing mutant human amyloid precursor protein (APPsw) and presenilin 1 (PS1ΔE9) genes, each independent causes of early-onset familial AD.

Methods

In this exploratory study, aged APP/PS1 rats were tested pre-, and post implantation with several stimulation parameters, i.e. unilateral- or bilateral-intermittent, and bilateral-continuous, while performing various behavioral tasks (open field, novel object recognition, and modified Barnes maze).

Results and Conclusion

Bilateral-intermittent NBM DBS allowed aged TG rats to perform better and maintain their performance longer in a spatial memory task, as compared to other conditions. These data support the notion that NBM DBS could be further refined in the clinic, thereby improving patient care.