bluuebunny/crossref_metadata_2025 huggingface dataset:
Early detection of recurrent medulloblastoma: the critical role of diffusion-weighted imaging
Authors: Aboian Mariam S , Kline Cassie N , Li Yi , Solomon David A , Felton Erin , Banerjee Anu , Braunstein Steve E , Mueller Sabine , Dillon William P , Cha Soonmee
Published: February 2018

Background

Imaging diagnosis of medulloblastoma recurrence relies heavily on identifying new contrast-enhancing lesions on surveillance imaging, with diffusion-weighted imaging (DWI) being used primarily for detection of complications. We propose that DWI is more sensitive in detecting distal and leptomeningeal recurrent medulloblastoma than T1-weighted postgadolinium imaging.

Methods

We identified 53 pediatric patients with medulloblastoma, 21 of whom developed definitive disease recurrence within the brain. MRI at diagnosis of recurrence and 6 months prior was evaluated for new lesions with reduced diffusion on DWI, contrast enhancement, size, and recurrence location.

Results

All recurrent medulloblastoma lesions demonstrated reduced diffusion. Apparent diffusion coefficient (ADC) measurements were statistically significantly lower (P = .00001) in recurrent lesions (mean=0.658, SD=0.072) as compared to contralateral normal region of interest (mean=0.923, SD=0.146). Sixteen patients (76.2%) with disease recurrence demonstrated contrast enhancement within the recurrent lesions. All 5 patients with nonenhancing recurrence demonstrated reduced diffusion, with a mean ADC of 0.695 ± 0.101 (normal=0.893 ± 0.100, P = .0027). While group 3 and group 4 molecular subtypes demonstrated distal recurrence more frequently, nonenhancing metastatic disease was found in all molecular subtypes.

Conclusion

Recurrent medulloblastoma lesions do not uniformly demonstrate contrast enhancement on MRI, but all demonstrate reduced diffusion. Our findings support that DWI is more sensitive than contrast enhancement for detection of medulloblastoma recurrence, particularly in cases of leptomeningeal nonenhancing disease and distal nonenhancing focal disease. As such, recurrent medulloblastoma can present as a reduced diffusion lesion in a patient with normal postgadolinium contrast MRI.
Splenic Infarction: An Under-recognized Complication of Infectious Mononucleosis?
Authors: Li Yan , George Ann , Arnaout Sami , Wang Jennifer P , Abraham George M
Published: February 2018

Splenic infarction is a rare complication of infectious mononucleosis. We describe 3 cases of splenic infarction attributed to infectious mononucleosis that we encountered within a 2-month period. We underscore the awareness of this potential complication of infectious mononucleosis and discuss the differential diagnosis of splenic infarction, including infectious etiologies. While symptomatic management is usually sufficient for infectious mononucleosis-associated splenic infarction, close monitoring for other complications, including splenic rupture, is mandated.
Modified Minimally Invasive Transforaminal Lumbar Interbody Fusion Technique Can Potentially Improve Safety of Interbody Graft Placement
Authors: Kurtom Khalid H , Towers Wendy S
Published: February 2018

BACKGROUND

Minimally invasive transforaminal lumbar interbody fusion (MITLIF) is a well-described procedure with excellent reported outcomes. A modification of interbody graft placement can potentially improve the ease and safety of this procedure.

OBJECTIVE

To describe a modification of the MITLIF graft placement and retrospectively review our experience including intraoperative and postoperative complications.

METHODS

Single surgeon, single institution, retrospective analysis of consecutive patients who underwent a modified MITLIF technique between November 2011 and December 2013. Hospital records including operative notes and discharge summaries were reviewed for patient demographics, surgical parameters including operative time and estimated blood loss, intraoperative complications including durotomy/cerebrospinal fluid leak, and postoperative outcomes including time before ambulation and length of stay were all reviewed and analyzed.

RESULTS

Eighty-three consecutive MITLIF patients; 71 underwent 1-level fusion and 12 had multilevel fusions. Average operative time for single level was 181 min; multilevel was 323 min. Average estimated blood loss was 140 mL. Time before ambulation was <1 d, average length of stay was 1.6 d. There were a total of 4 complications in this series (4.8%). There was zero incidence of durotomy or cerebrospinal fluid leak.

CONCLUSION

This modified MITLIF technique of maintaining the medial facet prior to discectomy and interbody graft placement can offer the minimally invasive spine surgeons increased assurance while placing the graft and potentially enhance the overall safety and efficacy of this approach. Surgeons utilizing this approach will have little difficulty utilizing this slight modification.
An ‘i’ for ani, a Truth for a Truth†
Authors: Leng Mary
Published: February 2018

Stewart Shapiro’s ante rem structuralism recognizes the structural or ‘algebraic’ aspects of mathematical practice while still offering a face-value semantics. Fictionalism, as a purely ‘algebraic’ approach, is held to be at a disadvantage, as compared with Shapiro’s structuralism, in not interpreting mathematics at face value. However, the face-value reading of mathematical singular terms has difficulty explaining how we can use such terms to pick out a unique referent in cases where the relevant mathematical structures admit non-trivial automorphisms. Shapiro offers a solution to this difficulty, but his solution, I argue, evens the score between Shapiro’s structuralism and fictionalism.
Recent advances in radiation oncology: multimodal targeting of high risk and recurrent prostate cancer
Authors: Kwok Young , Kaiser Adeel , Rice Stephanie R. , Cohen Randi , Mishra Mark
Published: February 2018

Purpose of review

The overview summarizes recent developments in radiation oncology for high risk and recurrent prostate cancer.

Recent findings

A number of well known phase III prostate hypofractionated radiation therapy (HFxRT) trials were finally published with long-term follow-ups. These trials demonstrate patterns of equivalent tumor control with several showing worse toxicity rates. The ASCENDE-RT randomized trial demonstrated the superiority of brachytherapy boost in intermediate and high-risk prostate cancer. Important randomized trials show a clear benefit to androgen deprivation therapy (ADT) in both intermediate-risk prostate cancer and postprostatectomy patients with rising PSA. Finally, the first randomized trial of metastasis-directed therapy showed a delay in time to ADT and biochemical failures in oligometastatic prostate cancer.

The use of brachytherapy boost in high-risk disease and ADT in locally recurrent cancer after prostatectomy are practice changing given the magnitude of benefit seen in the randomized trials. The benefit of metastasis-directed therapy in oligometastatic prostate cancer must be validated in a larger randomized trial. However, hypofractionated radiation therapy requires further long-term follow-up so that late toxicity risk can be accurately assessed before it becomes a standard of care in prostate cancer.
Diagnosis and Management of VTE in Pregnancy
Authors: McLEAN KELLEY C. , JAMES ANDRA H.
Published: February 2018

Venous thromboembolism is a leading cause of maternal death. Because of the low absolute frequency of events, however, outcome-based clinical data are limited. Consequently, clinicians must additionally rely both on published guidelines and on extrapolation of data from studies focused on nonpregnant individuals. The diagnosis and treatment of deep vein thrombosis, pulmonary embolism, and cerebral vein and dural sinus thrombosis are complicated by pregnancy, and often require modifications to standard diagnostic and treatment algorithms outside of pregnancy. Treatment of VTE in pregnant women is in particular need of future research.
Variability in Quality of Life Outcomes Following a Pulmonary Rehabilitation Program in Patients With COPD
Authors: Porto Elias F. , Castro Antonio A. M. , Cortopassi Felipe , de Souza Gerson F. , Jardim José R.
Published: February 2018

Purpose:

Pulmonary rehabilitation (PR) improves exercise tolerance in patients with chronic obstructive pulmonary disease. However, it is unclear why some patients do not improve quality of life during a training program. Our objective was to evaluate the differences between patients with chronic obstructive pulmonary disease who improve and those who do not improve quality of life during a pulmonary rehabilitation program.

Methods:

Seventy-three patients underwent a PR program. All patients trained at 80% (legs) and 50% (arms) of their maximum load. Incremental and endurance tests, 6-min walk test, and health-related quality of life with the St George Respiratory Questionnaire (SGRQ) were measured. We subdivided the groups based on a decrease ≥4 points in the pre- and post-PR SGRQ total score (G1); <4-point change in the SGRQ total score (G2); and an increase in scores ≥4 points (G3).

Results:

Exacerbation frequency (P = .004) and SGRQ total scores (P < .001) were lower in G1 and G2 than in G3. G1 (P = .0007) and G2 (P = .0005) significantly improved 6-min walk test distance. Before PR, G1 and G2 walked greater distances than G3 (P = .003); however, the difference was no longer significant after PR (P = .34). A significant load increase was seen after PR for the 3 groups (P < .05). We found a significant correlation between the SGRQ and the Charlson index (r = 0.78, P < .0001), exacerbation frequency (r = 0.72, P < .0001), and basal dyspnea index (r = −0.48, P < .0001).

Conclusion:

Patients whose quality of life did not improve after comprehensive PR presented a higher number of disease-related exacerbations with comorbidities.
Safety and Functionality of a Guidewire Fixator
Authors: Liungman Krister , Mani Kevin , Wanhainen Anders , Bosaeus Linus , Lachat Mario
Published: February 2018

Objective

A new endovascular tool, the Liungman Guidewire Fixator, has been developed to simplify endovascular treatment in complex aortic aneurysms. The device has been extensively tested in bench models and animal trials. To verify the safety and functionality demonstrated in the porcine model, the device was tested in ten patients undergoing endovascular aortic repair (EVAR) or fenestrated endovascular aortic repair (f-EVAR) treatment for abdominal aortic aneurysm.

Methods

The Liungman Guidewire Fixator consists of a braided stent-like, cylindrical structure with conical ends and a central channel for a 0.035” guidewire. When in use, it is slid along the guidewire and positioned in the target artery, where the Liungman Guidewire Fixator interacts with the arterial wall by anchoring the guidewire to the wall through a radial force. The Liungman Guidewire Fixator allows for uninterrupted blood flow passed the point of fixation. In this study, the Liungman Guidewire Fixator was tested in ten patients undergoing EVAR or f-EVAR treatment for abdominal aortic aneurysm. The device was deployed and retrieved crossover into the hypogastric artery, and the occurrence of thrombotic occlusion, arterial dissection, and vascular rupture or trauma was studied using angiography, as well as device ability to withstand guidewire tension.

Results

There were no instances of occlusion, dissection, or vascular trauma detected using angiography. In all cases, deployment and retrieval were successful, and the devices could withstand an applied tension of 3 N. In one instance, retrieval was challenging because of significant tortuosity, which was resolved by a coaxial catheterization.

Conclusions

Deployment was uneventful in all ten patients. Retrieval according to the intended instruction for use was performed in nine of the patients. In one patient, a coaxial catheterization was necessary. All devices withstood a retention force of 3 N.
Evolving Practice and Changing Phenotype in Pediatric Autoimmune Liver Disease
Authors: Singh Harveen , Balouch Fariha , Noble Charlton , Lewindon Peter
Published: February 2018

Objectives:

Autoimmune liver disease (AILD) incorporates primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and autoimmune sclerosing cholangitis (ASC). ASC is a condition that includes overlap of AIH and PSC. We investigate changes in practice in relation to diagnosis and phenotype over 2 time periods.

Methods:

Retrospective chart review was conducted from January 2000 to 2016. Data were divided into two 8‐year cohorts, CI and C2.

Results:

Data were collected in 75 children, 29 in 2000–2007 (C1) and 46 in 2008–2016 (C2). Presenting AILD type was AIH in 59%, ASC in 10%, and PSC in 31%. Final AILD type was AIH in 53%, ASC in 16%, and PSC in 31%. When comparing C1 to C2, those with AIH decreased (65% vs 45%) and those with ASC increased (14% vs 18%). Use of magnetic resonance cholangio‐pancreatography increased from 34% in C1 to 65% in C2. Advanced liver disease on biopsy was noted in 53% of all children at presentation. Only 5 female children progressed to liver transplant (3 ASC‐IBD [inflammatory bowel disease]; 1 PSC‐IBD; 1 AIH). Colonoscopy performance increased from 48% in C1 to 63% in C2 with diagnosis of AILD‐IBD increasing from 31% to 52%. Right‐sided disease was present in 46% and macroscopic rectal sparing in 36% of those with ulcerative colitis (UC). Colectomy was required in 3 children with large duct PSC‐IBD.

Conclusions:

PSC and ASC are increasing in relevance along with IBD and reflect increasing performance of magnetic resonance cholangio‐pancreatography and colonoscopy. Large duct PSC and ASC with IBD are risk factors for colectomy and along with female gender, for liver transplant.
Smartphone technology: a reliable and valid measure of knee movement in knee replacement
Authors: Castle Hannah , Kozak Kon , Sidhu Aman , Khan Riaz J.K. , Haebich Samantha , Bowden Vanessa , Fick Daniel P. , Goonatillake Hari
Published: February 2018

Knee range of motion (ROM) following a knee arthroplasty is an important clinical outcome that directly relates to the patient’s physical function. Smartphone technology has led to the creation of applications that can measure ROM. The aim was to determine the concurrent reliability and validity of the photo-based application ‘Dr Goniometer’ (DrG) compared with a universal goniometer performed by a clinician. A smartphone camera was used to take photographs of the knee in full flexion and full extension, and the images were sent by participants to a study phone. Participants then rated the ease of participation. To assess validity, the patient’s knee was measured by a clinician using a goniometer. To examine reliability, four clinicians assessed each image using DrG on four separate occasions spaced 1 week apart. A total of 60 images of knee ROM for 30 unicondylar or total knee arthroplasty were assessed. The goniometer and DrG showed strong correlations for flexion (r=0.94) and extension (r=0.90). DrG showed good intrarater reliability and excellent inter-rater reliability for flexion (intraclass correlation coefficient=0.990 and 0.990) and good reliability for extension (intraclass correlation coefficient=0.897 and 0.899). All participants found the process easy. DrG was proven to be a valid and reliable tool in measuring knee ROM following arthroplasty. Smartphone technology, in conjunction with patient-reported outcomes, offers an accurate and practical way to remotely monitor patients. Benefit may be found in differentiating those who need face-to-face clinical consult to those who do not.
Prognostic Implications of Pathological Response to Neoadjuvant Chemoradiation in Pathologic Stage III Rectal Cancer
Authors: Karagkounis Georgios , Thai Leo , Mace Adam G. , Wiland Homer , Pai Rish K. , Steele Scott R. , Church James M. , Kalady Matthew F.
Published: February 2018

Objective:

To evaluate the independent prognostic ability of the American Joint Committee on Cancer (AJCC) tumor regression scores within pathologic stage II and III rectal cancers.

Background:

Response to neoadjuvant chemoradiation (nCRT) has been debated as a biologic surrogate for tumor biology and prognosis in rectal cancer. AJCC regression scores have been shown to correlate with prognosis.

Methods:

Patient demographics, tumor characteristics, and AJCC scores (0 = complete response; 1 = isolated tumor cells remaining; 2 = residual cancer outgrown by fibrosis; 3 = extensive residual cancer) were assessed from 545 rectal cancer patients treated by nCRT followed by surgery at a single institution. Patients were classified as responders (score 0–2) or nonresponders (score 3). Survival analyses were performed using Cox proportional hazards models.

Results:

Of 545 cases, 123 and 182 were pathologic stage II and III, respectively. Median follow-up was 4.9 years. AJCC regression scores were not independently prognostic within stage II cancers. However, AJCC scores were strongly associated with prognosis within stage III cancers (nonresponse 5-year overall survival [OS] 27% vs 67%, P < 0.001). Stage III responders (N = 139, 76.4%) had similar outcomes to stage II (5-year OS 67% vs 74%, P = 0.89). Conversely, stage III nonresponders (N = 43, 23.6%) approached stage IV outcomes (5-year OS 27% vs 18%, P = 0.09). On multivariable analysis, nonresponse (hazard ratio 3.2, 95% confidence interval 1.7–6.2), along with positive margin, abdominoperineal resection, and no adjuvant chemotherapy administration were independently associated with worse OS.

Conclusions:

AJCC response score after nCRT is a novel prognostic factor in pathologic stage III rectal cancer and may guide surveillance and adjuvant therapy decisions.
Scientific risk communication about controversial issues influences public perceptions of scientists' political orientations and credibility
Authors: Vraga Emily , Myers Teresa , Kotcher John , Beall Lindsey , Maibach Ed
Published: February 2018

Many scientists communicate with the public about risks associated with scientific issues, but such communication may have unintended consequences for how the public views the political orientations and the credibility of the communicating scientist. We explore this possibility using an experiment with a nationally representative sample of Americans in the fall of 2015. We find that risk communication on controversial scientific issues sometimes influences perceptions of the political orientations and credibility of the communicating scientist when the scientist addresses the risks of issues associated with conservative or liberal groups. This relationship is moderated by participant political ideology, with liberals adjusting their perceptions of the scientists' political beliefs more substantially when the scientist addressed the risks of marijuana use when compared with other issues. Conservatives' political perceptions were less impacted by the issue context of the scientific risk communication but indirectly influenced credibility perceptions. Our results support a contextual model of audience interpretation of scientific risk communication. Scientists should be cognizant that audience members may make inferences about the communicating scientist's political orientations and credibility when they engage in risk communication efforts about controversial issues.
Multimodal integration and stimulus categorization in putative mushroom body output neurons of the honeybee
Authors: Strube-Bloss Martin F. , Rössler Wolfgang
Published: February 2018

Flowers attract pollinating insects like honeybees by sophisticated compositions of olfactory and visual cues. Using honeybees as a model to study olfactory–visual integration at the neuronal level, we focused on mushroom body (MB) output neurons (MBON). From a neuronal circuit perspective, MBONs represent a prominent level of sensory-modality convergence in the insect brain. We established an experimental design allowing electrophysiological characterization of olfactory, visual, as well as olfactory–visual induced activation of individual MBONs. Despite the obvious convergence of olfactory and visual pathways in the MB, we found numerous unimodal MBONs. However, a substantial proportion of MBONs (32%) responded to both modalities and thus integrated olfactory–visual information across MB input layers. In these neurons, representation of the olfactory–visual compound was significantly increased compared with that of single components, suggesting an additive, but nonlinear integration. Population analyses of olfactory–visual MBONs revealed three categories: (i) olfactory, (ii) visual and (iii) olfactory–visual compound stimuli. Interestingly, no significant differentiation was apparent regarding different stimulus qualities within these categories. We conclude that encoding of stimulus quality within a modality is largely completed at the level of MB input, and information at the MB output is integrated across modalities to efficiently categorize sensory information for downstream behavioural decision processing.
Ultra-fast cellular contractions in the epithelium ofT. adhaerensand the “active cohesion” hypothesis
Authors: Armon Shahaf , Storm Bull Matthew , Aranda-Diaz Andres , Prakash Manu
Published: February 2018

By definition of multi-cellularity, all animals need to keep their cells attached and intact, despite internal and external forces. Cohesion between epithelial cells provides this key feature. In order to better understand fundamental limits of this cohesion, we study the epithelium mechanics of an ultra-thin (~25 um) primitive marine animalTrichoplax adhaerens, composed essentially of two flat epithelial layers. With no known extra-cellular-matrix and no nerves or muscles,T. adhaerenswas claimed the “simplest known living animal”, yet is still capable of coordinated locomotion and behavior. Here we report the discovery of the fastest epithelial cellular contractions to date to be found inT. adhaerensdorsal epithelium (50% shrinkage of apical cell area within one second, at least an order of magnitude faster than known examples). Live imaging reveals emergent contractile patterns that are mostly sporadic single-cell events, but also include propagating contraction waves across the tissue. We show that cell contraction speed can be explained by current models of non-muscle actin-myosin bundles without load, while the tissue architecture and unique mechanical properties are softening the tissue, minimizing the load on a contracting cell. We propose a hypothesis, in which the physiological role of the contraction dynamics is to avoid tissue rupture (“active cohesion”), a novel concept that can be further applied to engineering of active materials.

One Sentence Summary

We report the fastest epithelial cell contractions known to date, show they fit the kinematics arising from current cytoskeletal models, and suggest the extreme tissue dynamics is a means to actively avoid rupture.
Mast Cells Enhance Sterile Inflammation in Chronic Nonbacterial Osteomyelitis
Authors: Young Stephanie , Sharma Namit , Lee Jae Hoon Peter , Chitu Violeta , Neumeister Volker , Sohr Elisabeth , Stanley E. Richard , Hedrich Christian M. , Craig Andrew W.B.
Published: February 2018

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease. While some patients exhibit bone lesions at single sites, most patients develop chronically active or recurrent bone inflammation at multiple sites, and are then diagnosed with recurrent multifocal osteomyelitis (CRMO). Chronic multifocal osteomyelitis (CMO) mice develop IL-1β-driven sterile bone lesions reminscent of severe CRMO. Mechanistically, CMO disease arises due to loss of PSTPIP2, a negative regulator of macrophages, osteoclasts and neutrophils. The goal of this study was to evaluate the potential involvement of mast cells in CMO/CRMO disease pathophysiology. Here, we show that mast cells accumulate in the inflamed tissues from CMO mice, and mast cell protease Mcpt1 was detected in the peripheral blood. The role of mast cells in CMO disease was investigated using a transgenic model of connective tissue mast cell depletion (Mcpt5-Cre:Rosa26-Stopfl/fl-DTa) that was crossed with CMO mice. The resulting CMO/MC-mice showed a significant delay in disease onset compared to age-matched CMO mice. At 5-6 months of age, CMO/MC- mice had fewer bone lesions and immune infiltration in the popliteal lymph nodes that drain the affected tail and paw tissues. To test the relevance of mast cells to human CRMO, we tested serum samples from a cohort of healthy controls or CRMO patients at diagnosis. Interestingly, mast cell chymase was elevated in CRMO patients as well as patients with oligoclonal juvenile arthritis. Tryptase-positive mast cells were also detected in bone lesions from CRMO patients as well as patients with bacterial osteomyelitis. Taken together, our results identify mast cells as cellular contributors to bone inflammation in CMO/CRMO. Observations of this study promise potential for mast cells and derived mediators as future biomarkers and/or therapeutic targets.
Emergence of the erythroid lineage from multipotent hematopoiesis
Authors: Khoramian Tusi Betsabeh , Wolock Samuel L. , Weinreb Caleb , Hwang Yung , Hidalgo Daniel , Zilionis Rapolas , Waisman Ari , Huh Jun , Klein Allon M. , Socolovsky Merav
Published: February 2018

Red cell formation begins with the hematopoietic stem cell, but the manner by which it gives rise to erythroid progenitors, and their subsequent developmental path, remain unclear. Here we combined single-cell transcriptomics of murine hematopoietic tissues with fate potential assays to infer a continuous yet hierarchical structure for the hematopoietic network. We define the erythroid differentiation trajectory as it emerges from multipotency and diverges from 6 other blood lineages. With the aid of a new flow-cytometric sorting strategy, we validated predicted cell fate potentials at the single cell level, revealing a coupling between erythroid and basophil/mast cell fates. We uncovered novel growth factor receptor regulators of the erythroid trajectory, including the proinflammatory IL-17RA, found to be a strong erythroid stimulator; and identified a global hematopoietic response to stress erythropoiesis. We further identified transcriptional and high-purity FACS gates for the complete isolation of all classically-defined erythroid burst-forming (BFU-e) and colony-forming progenitors (CFU-e), finding that they express a dedicated transcriptional program, distinct from that of terminally-differentiating erythroblasts. Intriguingly, profound remodeling of the cell cycle is intimately entwined with CFU-e developmental progression and with a sharp transcriptional switch that extinguishes the CFU-e stage and activates terminal differentiation. Underlying these results, our work showcases the utility of theoretic approaches linking transcriptomic data to predictive fate models, providing key insights into lineage developmentin vivo.
Emerging Evidence of Chromosome Folding by Loop Extrusion
Authors: Fudenberg Geoffrey , Abdennur Nezar , Imakaev Maxim , Goloborodko Anton , Mirny Leonid A.
Published: February 2018

Chromosome organization poses a remarkable physical problem with many biological consequences: how can molecular interactions between proteins at the nanometer scale organize micron-long chromatinized DNA molecules, insulating or facilitating interactions between specific genomic elements? The mechanism of active loop extrusion holds great promise for explaining interphase and mitotic chromosome folding, yet remains difficult to assay directly. We discuss predictions from our polymer models of loop extrusion with barrier elements, and review recent experimental studies that provide strong support for loop extrusion, focusing on perturbations to CTCF and cohesin assayed via Hi-C in interphase. Finally, we discuss a likely molecular mechanism of loop extrusion by SMC complexes.
High prevalence of the antibody against Syncytin-1 in schizophrenia
Authors: Hibi Yurina , Asamitsu Kaori , Matsumura Hiroyo , Sanda Takaomi , Nakahira Yuki , Arimoto Kenji , Nakanishi Shinsuke , Maekawa Kazunori , Akechi Tatsuo , Matsukawa Noriyuki , Fukaya Terutaka , Tomita Yutaka , Iijima Nariaki , Kato Hiroyuki , Okamoto Takashi
Published: February 2018

Both genetic and environmental factors have been considered causative agents for schizophrenia (SZ). However, no single gene has been shown responsible for the development of SZ. Furthermore, the pathophysiological roles of environmental factors including psychological stress, autoimmunity, and microbial infection have not been fully understood. Previous studies have suggested the involvement of one of the human endogenous retroviruses (HERVs), HERV-W, in SZ. In this study, prevalence of antibodies against the HERV-W Syncytin-1 protein was examined using a newly developed ELISA test. Fifty percent of patients with SZ (24 out of 48 cases) were antibody-positive, with a specificity of greater than 95% (less than 5% of control cases, 3 out of 79). No significant effect of medication was evident, nor did any SZ cases become seropositive after diagnosis. These findings indicate a possible involvement of HERV-W expression in the development of SZ and support its applicability to laboratory diagnoses.
Sequence-directed action of RSC remodeler and pioneer factors positions +1 nucleosome to facilitate transcription
Authors: Kubik Slawomir , O’Duibhir Eoghan , de Jonge Wim , Mattarocci Stefano , Albert Benjamin , Falcone Jean-Luc , Bruzzone Maria Jessica , Holstege Frank C.P. , Shore David
Published: February 2018

Accessible chromatin is important for RNA polymerase II recruitment and transcription initiation at eukaryotic promoters. We investigated the mechanistic links between promoter DNA sequence, nucleosome positioning and transcription. Our results indicate that precise positioning of the transcription start site-associated +1 nucleosome in yeast is critical for efficient TBP binding, and is driven by two key factors, the essential chromatin remodeler RSC and a small set of ubiquitous pioneer transcription factors. We find no evidence for recruitment of RSC by pioneer factors, but show instead that the strength and directionality of RSC action on nucleosomes depends upon the arrangement of two specific DNA motifs that promote its binding and nucleosome displacement activity at promoters. Thus, despite their widespread co-localization, RSC and pioneer factors predominantly act independently to generate accessible chromatin. Our results provide insight into how promoter DNA sequence instructs trans-acting factors to control nucleosome architecture and stimulate transcription initiation.
Standard operating procedure for somatic variant refinement of tumor sequencing data
Authors: Barnell Erica K. , Ronning Peter , Campbell Katie M. , Krysiak Kilannin , Ainscough Benjamin J. , Ramirez Cody , Spies Nick , Kunisaki Jason , Hundal Jasreet , Skidmore Zachary L. , Gomez Felicia , Trani Lee , Matlock Matthew , Wagner Alex H. , Swamidass S. Joshua , Griffith Malachi , Griffith Obi L.
Published: February 2018

Purpose

Manual review of aligned sequencing reads is required to develop a high-quality list of somatic variants from massively parallel sequencing data (MPS). Despite widespread use in analyzing MPS data, there has been little attempt to describe methods for manual review, resulting in high inter- and intra-lab variability in somatic variant detection and characterization of tumors.

Methods

Open source software was used to develop an optimal method for manual review setup. We also developed a systemic approach to visually inspect each variant during manual review.

Results

We present a standard operating procedures for somatic variant refinement for use by manual reviewers. The approach is enhanced through representative examples of 4 different manual review categories that indicate a reviewer’s confidence in the somatic variant call and 19 annotation tags that contextualize commonly observed sequencing patterns during manual review. Representative examples provide detailed instructions on how to classify variants during manual review to rectify lack of confidence in automated somatic variant detection.

Conclusion

Standardization of somatic variant refinement through systematization of manual review will improve the consistency and reproducibility of identifying true somatic variants after automated variant calling.
tarsal-less is expressed as a gap gene but has no gap gene phenotype in the moth midge Clogmia albipunctata
Authors: Jiménez-Guri Eva , Wotton Karl R. , Jaeger Johannes
Published: February 2018

Gap genes are involved in segment determination during early development of the vinegar fly Drosophila melanogaster and other dipteran insects (flies, midges, and mosquitoes). They are expressed in overlapping domains along the antero-posterior (A–P) axis of the blastoderm embryo. While gap domains cover the entire length of the A–P axis in Drosophila, there is a region in the blastoderm of the moth midge Clogmia albipunctata, which lacks canonical gap gene expression. Is a non-canonical gap gene functioning in this area? Here, we characterize tarsal-less (tal) in C. albipunctata. The homolog of tal in the flour beetle Tribolium castaneum (called milles-pattes, mlpt) is a bona fide gap gene. We find that Ca-tal is expressed in the region previously reported as lacking gap gene expression. Using RNA interference, we study the interaction of Ca-tal with gap genes. We show that Ca-tal is regulated by gap genes, but only has a very subtle effect on tailless (Catll), while not affecting other gap genes at all. Moreover, cuticle phenotypes of Ca-tal depleted embryos do not show any gap phenotype. We conclude that Ca-tal is expressed and regulated like a gap gene, but does not function as a gap gene in C. albipunctata.
FDAAA TrialsTracker: A live informatics tool to monitor compliance with FDA requirements to report clinical trial results
Authors: DeVito Nicholas J. , Bacon Seb , Goldacre Ben
Published: February 2018

Introduction

Non-publication of clinical trials results is an ongoing issue. In 2016 the US government updated the results reporting requirements to ClinicalTrials.gov for trials covered under the FDA Amendments Act 2007. We set out to develop and deliver an online tool which publicly monitors compliance with these reporting requirements, facilitates open public audit, and promotes accountability.

Methods

We conducted a review of the relevant legislation to extract the requirements on reporting results. Specific areas of the statutes were operationalized in code based on the results of our policy review, publicly available data from ClinicalTrials.gov, and communications with ClinicalTrials.gov staff. We developed methods to identify trials required to report results, using publicly available registry data; to incorporate additional relevant information such as key dates and trial sponsors; and to determine when each trial became due. This data was then used to construct a live tracking website.

Results

There were a number of administrative and technical hurdles to successful operationalization of our tracker. Decisions and assumptions related to overcoming these issues are detailed along with clarifications directly from ClinicalTrials.gov. The FDAAA TrialsTracker was successfully launched in February 2018 and provides users with an overview of results reporting compliance.

Discussion

Clinical trials continue to go unreported despite numerous guidelines, commitments, and legal frameworks intended to address this issue. In the absence of formal sanctions from the FDA and others, we argue tools such as ours - providing live data on trial reporting - can improve accountability and performance. In addition, our service helps sponsors identify their own individual trials that have not yet reported results: we therefore offer positive practical support for sponsors who wish to ensure that all their completed trials have reported.
A comment on“Species are not most abundant in the centre of their geographic range or climatic niche”
Authors: Soberón Jorge , Peterson A. Townsend , Osorio-Olvera Luis
Published: February 2018

A study recently published argued against a relationship between population density and position in geographic and environmental spaces. We found a number of methodological problems underlying the analysis. We discuss the main issues and conclude that these problems hinder a robust conclusion about the original question.
Stress response ofChironomus ripariusto changes in water temperature and oxygen concentration in a lowland stream
Authors: Manfrin Alessandro , Larsen Stefano , Scalici Massimiliano , Wuertz Sven , Monaghan Michael T.
Published: February 2018

The increasing impairment of lotic ecosystems has promoted a growing effort into assessing their ecological status by means of biological indicators. While community-based approaches have proven valuable to assess ecosystem integrity, they mostly reflect long-term changes and might not be suitable for tracking and monitoring short-term events. Responses to rapid changes in environmental conditions have been rarely studied under natural conditions. Biomarkers offer the benefit of integrating biological responses at different time scales. Here we used a field experiment to test how the synthesis of heat shock protein 70 (HSP70) and Haemoglobin (Hb) in laboratory-reared larvae ofChironomus riparius(Diptera, Chironomidae) were influenced by short-term changes to water temperature and oxygen concentration in a lowland stream. Our aim was to determine whether HSP70 mRNA expression and Hb content could be used as anin situ“early warning system” for freshwater habitats undergoing environmental change. HSP70 exhibited a clear response to changes in temperature measured over a one-day period, confirming its suitability as an indicator of environmental stress. Hb concentration was related to oxygen concentration, but not to temperature. Our findings support the hypothesis that depletion in oxygen induces Hb synthesis inC. ripariuslarvae. Because tolerance to low oxygen is not only related to total Hb, but also to a more efficient uptake (binding to Hb, e.g. Bohr effect) and release of oxygen to the cell (Root effect), we cannot discern from our data whether increased efficiency played a role. We suggest thatC. ripariusis a suitable model organism for monitoring sub-lethal stress in the field and that the approach could be applied to other species as more genomic data are available for non-model organisms.
Characterizing protein-DNA binding event subtypes in ChIP-exo data
Authors: Yamada Naomi , Lai William K.M. , Farrell Nina , Pugh B. Franklin , Mahony Shaun
Published: February 2018

Motivation

Regulatory proteins associate with the genome either by directly binding cognate DNA motifs or via protein-protein interactions with other regulators. Each recruitment mechanism may be associated with distinct motifs and may also result in distinct characteristic patterns in high-resolution protein-DNA binding assays. For example, the ChIP-exo protocol precisely characterizes protein-DNA crosslinking patterns by combining chromatin immunoprecipitation (ChIP) with 5’ → 3’ exonuclease digestion. Since different regulatory complexes will result in different protein-DNA crosslinking signatures, analysis of ChIP-exo tag enrichment patterns should enable detection of multiple protein-DNA binding modes for a given regulatory protein. However, current ChIP-exo analysis methods either treat all binding events as being of a uniform type or rely on motifs to cluster binding events into subtypes.

Results

To systematically detect multiple protein-DNA interaction modes in a single ChIP-exo experiment, we introduce the ChIP-exo mixture model (ChExMix). ChExMix probabilistically models the genomic locations and subtype memberships of binding events using both ChIP-exo tag distribution patterns and DNA motifs. We demonstrate that ChExMix achieves accurate detection and classification of binding event subtypes using in silico mixed ChIP-exo data. We further demonstrate the unique analysis abilities of ChExMix using a collection of ChIP-exo experiments that profile the binding of key transcription factors in MCF-7 cells. In these data, ChExMix identifies possible recruitment mechanisms of FoxA1 and ERα, thus demonstrating that ChExMix can effectively stratify ChIP-exo binding events into biologically meaningful subtypes.

Availability

ChExMix is available from https://github.com/seqcode/chexmix

Contact

mahony@psu.edu
Growth tradeoffs produce complex microbial communities on a single limiting resource
Authors: Manhart Michael , Shakhnovich Eugene I.
Published: February 2018

The relationship between the dynamics of a community and its constituent pairwise interactions is a fundamental problem in ecology. Higher-order ecological effects beyond pairwise interactions may be key to complex ecosystems, but mechanisms to produce these effects remain poorly understood. Here we show that higher-order effects can arise from variation in multiple microbial growth traits, such as lag times and growth rates, on a single limiting resource with no other interactions. These effects produce a range of ecological phenomena: an unlimited number of strains can exhibit multi stability and neutral coexistence, potentially with a single keystone strain; strains that coexist in pairs do not coexist all together; and the champion of all pairwise competitions may not dominate in a mixed community. Since variation in multiple growth traits is ubiquitous in microbial populations due to pleiotropy and non-genetic variation, our results indicate these higher-order effects may also be widespread, especially in laboratory ecology and evolution experiments.
Quantifying configuration-sampling error in Langevin simulations of complex molecular systems
Authors: Fass Josh , Sivak David A. , Crooks Gavin E. , Beauchamp Kyle A. , Leimkuhler Benedict , Chodera John D.
Published: February 2018

While Langevin integrators are popular in the study of equilibrium properties of complex systems, it is challenging to estimate the timestep-induced discretization error: the degree to which the sampled phase-space or configuration-space probability density departs from the desired target density due to the use of a finite integration timestep. In [1], Sivaket al. introduced a convenient approach to approximating a natural measure of error between the sampled density and the target equilibrium density, the KL divergence, inphase space, but did not specifically address the issue ofconfiguration-space properties, which are much more commonly of interest in molecular simulations. Here, we introduce a variant of this near-equilibrium estimator capable of measuring the error in the configuration-space marginal density, validating it against a complex but exact nested Monte Carlo estimator to show that it reproduces the KL divergence with high fidelity. To illustrate its utility, we employ this new near-equilibrium estimator to assess a claim that a recently proposed Langevin integrator introduces extremely small configuration-space density errors up to the stability limit at no extra computational expense. Finally, we show how this approach to quantifying sampling bias can be applied to a wide variety of stochastic integrators by following a straightforward procedure to compute the appropriate shadow work, and describe how it can be extended to quantify the error in arbitrary marginal or conditional distributions of interest.
Control of mRNA decapping by autoinhibition
Authors: Paquette David R , Tibble Ryan W , Daifuku Tristan S , Gross John D
Published: February 2018

5’ mediated cytoplasmic RNA decay is a conserved cellular process in eukaryotes. While the functions of the structured core domains in this pathway are understood, the role of abundant intrinsically disordered regions (IDRs) is lacking. Here we reconstitute the Dcp1:Dcp2 complex containing a portion of the disordered C-terminus and show its activity is autoinhibited by linear interaction motifs. Enhancers of decapping (Edc) 1 and 3 cooperate to activate decapping by different mechanisms: Edc3 alleviates auto-inhibition by binding IDRs and destabilizing an inactive form of the enzyme, whereas Edc1 stabilizes the transition state for catalysis. Both activators are required to fully stimulate an autoinhibited Dcp1:Dcp2 as Edc1 alone cannot overcome the decrease in activity attributed to the C-terminal extension. Our data provide a mechanistic framework for combinatorial control of decapping by protein cofactors, a principle that is likely conserved in multiple 5’ mRNA decay pathways.
The axon initial segment drives the neuron’s extracellular action potential
Authors: Bakkum Douglas J. , Radivojevic Milos , Obien Marie Engelene J. , Jaeckel David , Frey Urs , Takahashi Hirokazu , Hierlemann Andreas
Published: February 2018

Extracellular voltage fields produced by a neuron’s action potentials provide a primary means for studying neuron function, yet their biophysical sources remain ambiguous. The neuron’s soma and dendrites are thought to drive the extracellular action potential (EAP), while the axon is usually ignored. However, by recording voltages of single neurons in dissociated rat cortical cultures and Purkinje cells in acute mouse cerebellar slices at hundreds of sites, we find instead that the axon initial segment dominates the EAP, and, surprisingly, the soma shows little or no influence. As expected, this signal has negative polarity (charge entering the cell) and initiates at the distal end. Interestingly, signals with positive polarity (charge exiting the cell) occur near some but not all dendritic branches and occur after a delay. Such basic knowledge about which neuronal compartments contribute to the extracellular voltage field is important for interpreting results from all electrical readout schemes. Moreover, this finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.

Key points summary

The neuron’s soma and dendrites are thought to give rise to its extracellular voltage signal, while signals from the axon are usually considered negligible.

Instead, we found that the largest amplitude of the extracellular signal originates from the axon initial segment, not from the soma.

This finding shows that changes in the AIS position and function can be observed in high spatiotemporal detail by means of high-density extracellular electrophysiology.

Abbreviations

ACSF

artificial cerebrospinal fluid

AIS

axon initial segment

AnkG

ankyrin-G

CMOS

complementary-metal-oxide-semiconductor

DMEM

Dulbecco’s modified eagle medium

EAP

extracellular action potential

GAD67-GFP

glutamic acid decarboxylase 67-green fluorescent protein

MAP2

microtubule-associated protein 2.
Mavacamten stabilizes a folded-back sequestered super-relaxed state of β-cardiac myosin
Authors: Anderson Robert L. , Trivedi Darshan V. , Sarkar Saswata S. , Henze Marcus , Ma Weikang , Gong Henry , Rogers Christopher S. , Wong Fiona L. , Morck Makenna M. , Seidman Jonathan G. , Ruppel Kathleen M. , Irving Thomas C. , Cooke Roger , Green Eric M. , Spudich James A.
Published: February 2018

Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity and ATPase activityof myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative modelpositsthat mutations in myosin affect the stability ofa sequestered, super-relaxed state (SRX) of the proteinwith very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here, using a combination of biochemical and structural approaches, we show that purified myosin enters aSRX thatcorresponds to a folded-back conformation, which in muscle fibersresults insequestration of heads around the thick filament backbone. Mutations that cause HCM destabilize this state, while the small molecule mavacamtenpromotes it. These findings provide a biochemical and structural link between the genetics and physiology ofcardiomyopathywith implications for therapeutic strategies.