bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Vertically Yoked Prisms on Binocular Vision and Accommodation
Authors: Schmid Katrina L. , Beavis Stephanie D. , Wallace Sophia I. , Chen Joy , Chien Yi-Tang , Nguyen Terry , Tran Amy , Varnas Saulius R. , Atchison David A.
Published: May 2019

SIGNIFICANCE

Vertically yoked prisms have been used in treatment of binocular vision dysfunction despite minimal supporting evidence. In people with normal binocular vision, the impact on phorias has been assessed but not the impact on accommodation, accommodation vergence interactions, or the horopter. We found that vertically yoked prisms have minor effects during short-term wear in young adults.

PURPOSE

The purpose of this study was to determine effects of vertically yoked prisms on accommodative response and several binocular vision tasks.

METHODS

There were 45 participants aged 18 to 24 years. The 23 myopes wore distance-corrected soft contact lenses. In a random arrangement, each person wore spectacles containing planopower lenses with either 8 Δ base-up, 4 Δ base-up, zero, 4 Δ base-down, and 8 Δ base-down prisms. Before spectacle wear, baseline measurements of near heterophoria, accommodation response, negative and positive relative accommodations, fusional vergence, and Nonius-horopter spatial perception were taken. Measurements were repeated after a 40-minute wear, spectacles were removed, and tests were performed 20 minutes later. On a 22-participant subset, on a separate occasion, measurements of heterophoria, accommodation response, and relative accommodation were made immediately after spectacles were fitted.

RESULTS

Most changes relative to baseline were not significant. Where effects occurred, these were nearly all associated with prism presence rather than adaptation. There were significant effects on accommodation response, but these seem to be refraction effects produced by pantoscopic tilt–induced power changes rather than perceptual effects altering accommodation. There were statistically significant effects on negative relative accommodation (P < .01), with zero prism giving more negative relative accommodation than 8 Δ base-down prisms. Tendencies were noted for prisms to move horopter limits toward the observer. Effects were small and likely not of clinical relevance.

CONCLUSIONS

Vertically yoked prisms have minor effects on accommodation and binocular vision, at least during short-term wear in young adults with normal binocular vision.
Analysis of Telomere Lengths in p53 Signatures and Incidental Serous Tubal Intraepithelial Carcinomas Without Concurrent Ovarian Cancer
Authors: Asaka Shiho , Davis Christine , Lin Shiou-Fu , Wang Tian-Li , Heaphy Christopher M. , Shih Ie-Ming
Published: May 2019

Telomere alterations represent one of the major molecular changes in the development of human cancer. We have previously reported that telomere lengths in most serous tubal intraepithelial carcinomas (STIC) are shorter than they are in ovarian high-grade serous carcinomas (HGSC) or in normal-appearing fallopian tube epithelium from the same patients. However, it remains critical to determine if similar telomere alterations occur in TP53-mutated but histologically unremarkable “p53 signature” lesions, as well as incidental STICs without concurrent HGSC. In this study, we quantitatively measured telomere lengths by performing telomere-specific fluorescence in situ hybridization in conjunction with p53 immunolabeling in 15 p53 signatures and 30 incidental STICs without concurrent HGSC. We compared these new results with our previous data in paired STICs and concurrent HGSCs. We found that most p53 signatures (80%) and incidental STICs without HGSC (77%) exhibited significant telomere shortening compared with adjacent normal-appearing fallopian tube epithelium (P<0.01). Interestingly, however, p53 signatures and incidental STICs without HGSC displayed longer telomeres and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC (P<0.001). These findings indicate that telomere shortening occurs in p53 signatures, the earliest precancer lesion. Moreover, incidental STICs without concurrent HGSC are indeed similar to p53 signatures as they have less telomere shortening and less cell-to-cell telomere length heterogeneity than STICs associated with HGSC.
Use of Decision Analysis and Economic Evaluation in Upper Extremity Surgery: A Systematic Review
Authors: Safran Tyler , Retrouvey Helene , Gorsky Kevin , Baltzer Heather L.
Published: May 2019

Background:

Decision analysis allows clinicians to apply evidence-based medicine to guide objective decisions in uncertain scenarios. There is no comprehensive review summarizing the various decision analysis tools used. The authors aimed to appraise and review the decision analytic models used in hand surgery.

Methods:

A search of English articles on the PubMed, Ovid, and Embase databases was performed. All articles, regardless of date of publishing, were considered. Two reviewers, based on strict inclusion criteria, independently assessed each article.

Results:

The search resulted in 5525 abstracts, which yielded 30 studies that met inclusion criteria. Included studies were grouped according to medical indications, with scaphoid fractures (n = 6) and carpal tunnel syndrome (n = 5) being the most commonly reported. Included articles used decision analysis (n = 15) and/or economic analyses (n = 23) to discuss diagnostic strategies or compare treatments. The three most common outcomes reported were utility (n = 12), cost per quality-adjusted life-year (n = 16), and quality-adjusted life-years (n = 16). The decision analysis models compared diagnostic strategies, management options, and novel treatments.

Conclusions:

Decision analysis is increasingly popular in hand surgery. It is useful for comparing surgical strategies through evaluation of quality-of-life outcomes and costing data. The most common model was a simple decision tree. The quality of decision analysis models can be improved with the addition of sensitivity analysis. Surgeons should be familiar with the principles of decision analysis, so that complex decisions can be evaluated using rigorous probabilistic models that combine risks and benefits of multiple strategies.
Interaction of Adipose-Derived Stromal Cells with Breast Cancer Cell Lines
Authors: Teufelsbauer Maryana , Rath Barbara , Moser Doris , Haslik Werner , Huk Ihor , Hamilton Gerhard
Published: May 2019

Background:

Assisted lipotransfer for breast reconstruction involves the isolation and supplementation of adipose-derived stromal cells. This procedure has raised concerns regarding safety with respect to promotion of tumor growth and relapse. Several in vitro and animal experimental studies have indicated increased survival, growth, and invasive characteristics of breast cancer cells on interaction with adipose-derived stromal cells. These results seem to be in poor concordance with clinical observations of a low rate of cancer recurrences after assisted lipotransfer.

Methods:

The authors investigated the effects of adipose-derived stromal cells and adipose-derived stromal cells differentiated into adipocytes and fibroblasts on five breast cancer cell lines (i.e., T47D, MCF-7, BT20, MDA-MB-231, and ZR-75-1) and MCF-10A, a nonmalignant counterpart.

Results:

Conditioned media of adipose-derived stromal cells stimulated the proliferation of breast cancer cell lines depending on the individual adipose-derived stromal cell–breast cancer cell line combination. Conditioned media of adipose-derived stromal cells differentiated into adipocytes gave a lower response, and conditioned media of fibroblasts were also active. A putative cancer stem cell–like phenotype was not increased by adipose-derived stromal cell–conditioned media, no physical interaction of cancer cells with adipose-derived stromal cells was detectable on scanning electron microscopy, and cell migration was not enhanced. Adipogenic differentiation of adipose-derived stromal cells indicated that hepatocyte growth factor, insulin-like growth factor-binding protein-3, insulin-like growth factor-binding protein-6, interleukin-6, CCL2/MCP-1, and macrophage colony-stimulating factor are not linked to the proliferative activity of conditioned media.

Conclusion:

The results indicate that the adipose-derived stromal cells used for assisted lipotransfer are not expected to increase the risk of tumor recurrence to a major degree in correspondence with the clinical observation of the affected breast cancer patients.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, V.
Frustration and Emotional Regulation in Nonsyndromic Craniosynostosis: A Functional Magnetic Resonance Imaging Study
Authors: Wu Robin T. , Yang Jenny F. , Zucconi William , Lacadie Cheryl , Swallow Matthew S. , Sun Alexander H. , Eilbott Jeffrey , Mayes Linda C. , Steinbacher Derek M. , Pelphrey Kevin , Persing John A.
Published: May 2019

Background:

Nonsyndromic craniosynostosis may manifest with complex behavioral, attentional, and emotional sequelae. The authors characterized higher level brain connectivity in adolescent nonsyndromic craniosynostosis patients in response to emotional frustration.

Methods:

Surgically corrected patients older than 9 years with nonsyndromic craniosynostosis were age/sex/handedness matched to controls. Patients participated in a “go/no-go” task, structured as win/lose/recovery paradigms. BioImage Suite was used to analyze whole-brain intrinsic connectivity between tasks with cluster-corrected group-level t maps. A value of p < 0.05 was significant.

Results:

Seven unilateral coronal (average age, 12.2 years), six metopic (average age, 11.5 years), and controls were included. Unilateral coronal had worse emotional regulation scores on the Behavior Rating Inventory of Executive Function survey (p = 0.065) and performed poorly on the go/no-go task (p < 0.001). Metopic had four regions of interest, with the majority having decreased activity compared with controls, and few differences between tasks. Unilateral coronal patients had 11 regions of interest; the majority decreased during the win and lose conditions, but all increased during the recovery condition. Metopic patients had decreased blood oxygenation level– dependent signal in the posterior cingulate (p = 0.017) and middle temporal gyrus (p = 0.042). Unilateral coronal had decreased signal in the posterior cingulate (p = 0.023), middle temporal gyrus (p = 0.027), and thalamus (p = 0.033), but increased signal in the cuneus (p = 0.009) and cerebellum (p = 0.009). Right unilateral coronal, but not metopic/controls, had increased right brain activity in the caudate (p = 0.030), thalamus (p = 0.011), temporal lobe (p = 0.012), and cerebellum (p = 0.029).

Conclusions:

Unilateral coronal patients may have emotional dysregulation in response to frustration, whereas metopic patients may have attenuated emotional reactions. Evidence of right unilateral coronal brain laterality suggests that the area of suture fusion may contribute to the mechanism of dysfunction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, II.
Expression of Components of the Renin-Angiotensin System by the Embryonic Stem Cell–Like Population within Keloid Lesions
Authors: Humphries Hugo , Brasch Helen D. , van Schaijik Bede , Tan Swee T. , Itinteang Tinte
Published: May 2019

Background:

We investigated expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 by the embryonic stem cell-like population on the endothelium of the microvessels and perivascular cells within keloid-associated lymphoid tissues.

Methods:

Immunohistochemical staining for prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 was performed on 11 formalin-fixed, paraffin-embedded sections of keloid tissue samples. Immunofluorescence staining was performed on three keloid tissue samples by co-staining with OCT4, CD34, ERG, and tryptase. Real-time quantitative polymerase chain reaction was performed on five keloid tissue samples and four keloid-derived primary cell lines. Western blotting was performed on the four keloid-derived primary cell lines for mRNA and protein expression of these proteins, respectively.

Results:

Immunohistochemical and immunofluorescence staining showed expression of prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 in all 11 keloid tissue samples. Prorenin receptor and angiotensin II receptor 1 were expressed on the endothelium and the pericyte layer of the microvessels and perivascular cells, angiotensin II receptor 2 was localized to the endothelium of the microvessels and the tryptase-positive perivascular cells, and angiotensin-converting enzyme was localized to the endothelium of the microvessel, within the keloid-associated lymphoid tissues. Real-time quantitative polymerase chain reaction showed transcripts of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid tissue samples and keloid-derived primary cell lines, whereas angiotensin II receptor 2 was detected in keloid tissue samples only. Western blotting confirmed the presence of prorenin receptor, angiotensin-converting enzyme, and angiotensin II receptor 1 in the keloid-derived primary cell lines.

Conclusion:

Prorenin receptor, angiotensin-converting enzyme, angiotensin II receptor 1, and angiotensin II receptor 2 were expressed by the embryonic stem cell–like population within the keloid-associated lymphoid tissues, suggesting that this primitive population may be a potential therapeutic target by modulation of the renin-angiotensin system.
Multifocal Meningiomas Mimicking Dural-Based Intracranial Metastases at 18F-Fluciclovine PET/CT
Authors: Manganaro Mark S. , Millet John D. , Manganaro Matthew S.
Published: May 2019

A 78-year-old man with biochemically recurrent prostate adenocarcinoma (prostate-specific antigen, 2.3 ng/mL) but without detectable disease in the chest, abdomen, or pelvis at conventional CT imaging or in the bones at 99mTc-MDP scintigraphy underwent 18F-fluciclovine (anti–1-amino-3-18F-fluorocyclobutane-1-carboxylic acid) PET/CT to evaluate for occult recurrent or metastatic disease. Imaging identified intense radiotracer uptake within 3 dural-based lesions along the left cerebral convexity. Subsequent MRI and biopsy confirmed multifocal World Health Organization grade 2 atypical meningiomas. Focal intracranial radiotracer uptake at 18F-fluciclovine PET/CT may create a diagnostic dilemma as incidental meningiomas can mimic intracranial metastases.
Primary Spinal Poorly Differentiated Neuroendocrine Tumor Displayed on FDG PET/CT
Authors: Shen Guohua , Ma Huan , Pan Lili , Su Minggang , Kuang Anren
Published: May 2019

18F-FDG PET/CT imaging provides valuable information in the evaluation and staging of spinal tumors. Herein, we report the case of a 57-year-old man who presented with a sudden paraplegia below the fifth thoracic vertebra due to cord compression of a spinal lesion. After spinal canal decompression and spinal lesion biopsy, the diagnosis was a poorly differentiated neuroendocrine tumor. Subsequent PET/CT revealed that it was a primary site, showing intense FDG uptake. He was eventually referred for palliative radiotherapy.
Factors Influencing the Impact of Depressive Symptoms on Physical Functional Capacity After Cardiac Rehabilitation
Authors: Wierenga Kelly L. , Moore Shirley M. , Liu Jintao , Sattar Abdus
Published: May 2019

Purpose

This study aims to determine (1) if depressive symptoms in the year following completion of cardiac rehabilitation impact physical functional capacity and (2) if exercise, perceived benefits and barriers, self-efficacy, and social support moderate this relationship.

Design

This longitudinal correlational secondary data analysis included 379 cardiovascular rehabilitation patients.

Methods

Participants completed measures of depression and potential moderating variables at baseline, 2 months, 6 months, and 12 months and 6-minute work test at baseline and 12 months and wore heart rate monitors to measure exercise for 12 months.

Findings

Poorer physical functional capacity was predicted by depressed mood score. This relationship was moderated by the percentage of time exercising in target heart rate zone and family support of exercise, but not by perceived benefits and barriers or self-efficacy for exercise.

Conclusions

Depressive symptoms negatively impact physical functional capacity, and this relationship is moderated by family support and the percentage of time exercising in target heart rate zone.

Clinical Relevance

Improving percentage of time exercising in target heart rate zone may be a mechanism by which patients with depressed mood can optimize physical functional capacity.
Computed Tomography-guided Cryoablation for Adrenal Pheochromocytoma: Safety and Clinical Effectiveness
Authors: Zhang Wei , Shi Yi-Bing , Zhuang Zhi-Xiang , Wang Jiu-Ping , Sun Li-Jun , Fu Yu-Fei
Published: May 2019

Purpose:

To evaluate the safety and clinical effectiveness of computed tomography (CT)-guided cryoablation for adrenal pheochromocytoma (AP).

Materials and Methods:

From July 2015 to October 2018, we observed 8 patients that underwent CT-guided cryoablation for AP. The blood pressure and pulse before treatment did not exceed 150/90 mm Hg and 90 times/min, respectively. Complete ablation rate, clinical success rate, and long-term outcomes were analyzed.

Results:

A total of 8 patients with 8 APs were treated by CT-guided cryoablation. The mean duration of the procedure was 67.5±4.6 minutes. No patient achieved complete ablation, yet the clinical success rate was 100%. The mean metanephrine decreased from 61.7±11.1 to 2.0±1.1 nmol/L (P<0.001). Hypertensive crisis was found in 5 (67.5%) patients during the procedure. During a mean follow-up of 16.9±13.4 months, no patient experienced tumor progression.

Conclusion:

CT-guided cryoablation is an effective method for patients with AP.
Routine Colonoscopy After Acute Diverticulitis: is it Warranted?
Authors: Ng Zi Qin , Moe Kyaw Soe , Wijesuriya Ruwan
Published: May 2019

Purpose:

Recent evidence suggests routine colonoscopy after acute diverticulitis is not necessary but remains debatable. The aim of this study was to investigate the incidence of follow-up colonoscopic finding of adenoma, advanced neoplastic lesion, and adenocarcinoma after diverticulitis.

Materials and Methods:

A retrospective review of all cases of acute diverticulitis admitted from November 2015 to April 2018 was performed. Data collected included demographics, computed tomography (CT) findings, and findings of the follow-up colonoscopy within 12 months.

Results:

A total of 368 patients were admitted for acute diverticulitis. A total of 366 patients underwent CT scan for diagnosis. Of whom, 185 patients (50.5%) had a follow-up colonoscopy; 115 (31.4%) did not have a follow-up colonoscopy, and the remaining have had a recent colonoscopy. The overall incidence of adenomas was 25.9% (n=48) and advanced colonic neoplasia 1.62% (n=3) in patients who underwent follow-up colonoscopy.

Conclusions:

The finding of advanced colonic neoplasia in follow-up colonoscopy after an acute episode of CT-proven diverticulitis is equivalent to, or less than, that of the population colorectal cancer screening program. Routine colonoscopy is not necessary unless there are other concerning symptoms/CT findings.
Development and Preliminary Evaluation of IRD-1-2-3: An Animated Video to Inform Transplant Candidates About Increased Risk Donor Kidneys
Authors: Kayler Liise K. , Majumder Monami , Dolph Beth , Cobler-Lichter Michael , Cadzow Renee , Feeley Thomas H.
Published: May 2019

Background.

Current educational interventions about increased risk donors (IRDs) are less effective in improving knowledge among African American (AA) kidney transplant candidates compared to other races. We aimed to develop an IRD educational animated video culturally responsive to AAs and conduct feasibility testing.

Methods.

Between May 1, 2018, and June 25, 2018, we iteratively refined a culturally targeted video for AAs with input from multiple stakeholders. We then conducted a one group pre-post study between June 28, 2018, and October 29, 2018, with 40 kidney transplant candidates to assess the feasibility and acceptability of the video to improve participant knowledge and obtain feedback about IRD understanding, self-efficacy, and willingness. A mixed population was chosen to obtain race-specific acceptability data and efficacy estimates to inform a larger study.

Results.

Three themes emerged and informed video development; misattribution of IRD to kidney quality, IRD terminology as a barrier to meaningful understanding, and variable reactions to a 1:1000 risk estimate. The study cohort was 50% AA. Median IRD knowledge increased from 5 to 7.5 (P = 0.001) overall and from 5 to 7 (P < 0.001) among AAs. The frequency of positive responses increased pre-post video for understanding of (23% vs 83%, P < 0.001), self-efficacy to decide about (38% vs 70%, P < 0.001), and willingness to accept IRD kidneys (25% vs 72%, P < 0.001). Over 90% of participants provided positive ratings on each of the 6 acceptability items.

Conclusions.

A culturally responsive IRD educational video was developed in collaboration with key stakeholders. Quantitative results indicate the video was acceptable and promising to impact IRD knowledge among AA and non-AA kidney transplant candidates.
Intranasal Dexmedetomidine for Sedation During Magnetoencephalography
Authors: Tenney Jeffrey R. , Miller Jeffrey W. , Rose Douglas F.
Published: May 2019

Purpose:

Magnetoencephalography (MEG) is a noninvasive tool used clinically for presurgical evaluation of patients with medically intractable epilepsy. These recordings require patients to lie still for prolonged periods of time in a magnetically shielded room. Children or uncooperative adults with epilepsy may require sedation to reduce movement artefact and obtain high-quality recordings. Potential challenges related to the use of total intravenous anesthesia in the MEG environment include limited access to the patient's airway, remote location, suppression of cortical activity, and increased patient care expenses. We report our experience with intranasal dexmedetomidine as sedation for intractable epilepsy patients undergoing MEG.

Methods:

Sleep deprivation occurred the night before MEG testing. Intranasal dexmedetomidine (2 μg/kg) was administered and oxygen saturation, blood pressure, and pulse rate were recorded continuously on a monitor outside the magnetically shielded room. A recording of spontaneous neuromagnetic activity was immediately followed by median nerve electrical stimulation.

Results:

Twenty-six patients (mean age 12.2 ± 4.2 years) with medically intractable epilepsy were recorded using this protocol. There were no failures of sedation, and although patients experienced transient bradycardia, none required intervention and the recording did not need to be stopped. In all cases, artefact-free MEG recordings were obtained with sufficient interictal discharges available for source analysis.

Conclusions:

Our experience suggests that intranasal dexmedetomidine is an advantageous sedation option for children and adults with intractable epilepsy who are undergoing MEG. Further research is needed to determine the best ways to apply these methods to younger children and those with developmental disabilities.
Neural dynamics indicate parallel integration of environmental and self-motion information by place and grid cells
Authors: Laptev Dmitri , Burgess Neil
Published: May 2019

Place cells and grid cells in the hippocampal formation are thought to integrate sensory and self-motion information into a representation of estimated spatial location, but the precise mechanism is unknown. We simulated a parallel attractor system in which place cells form an attractor network driven by environmental inputs and grid cells form an attractor network performing path integration driven by self-motion, with inter-connections between them allowing both types of input to influence firing in both ensembles. We show that such a system is needed to explain the spatial patterns and temporal dynamics of place cell firing when rats run on a linear track in which the familiar correspondence between environmental and self-motion inputs is changed (Gothard et al., 1996b; Redish et al., 2000). In contrast, the alternative architecture of a single recurrent network of place cells (performing path integration and receiving environmental inputs) cannot reproduce the place cell firing dynamics. These results support the hypothesis that grid and place cells provide two different but complementary attractor representations (based on self-motion and environmental sensory inputs respectively). Our results also indicate the specific neural mechanism and main predictors of hippocampal map realignment and make predictions for future studies.
Music Perception in Acquired Prosopagnosia: An Anterior Temporal Syndrome for Faces, Voices and Music
Authors: Barton Jason J S , Stubbs Jacob L , Paquette Sebastien , Duchaine Brad , Schlaug Gottfried , Corrow Sherryse L
Published: May 2019

Background

Acquired prosopagnosia is often associated with other deficits, such as dyschromatopsia and topographagnosia, from damage to adjacent perceptual networks. A recent study showed that some subjects with developmental prosopagnosia also have congenital amusia, but problems with music perception have not been described in the acquired variant.

Objective

Our goal was to determine if music perception was also impaired in subjects with acquired prosopagnosia, and if so, its anatomic correlate.

Methods

We studied eight subjects with acquired prosopagnosia, all of whom had extensive neuropsychological and neuroimaging testing. They performed a battery of tests evaluating pitch and rhythm processing, including the Montréal Battery for the Evaluation of Amusia.

Results

Three of eight subjects with acquired prosopagnosia had impaired musical pitch perception while rhythm perception was spared. Two of the three also showed reduced musical memory. These three reported alterations in their emotional experience of music: one reported music anhedonia and aversion, while the remaining two had changes consistent with musicophilia. The lesions of these three subjects affected the right or bilateral temporal poles as well as the right amygdala and insula. None of the three prosopagnosic subjects with lesions limited to the inferior occipitotemporal cortex had impaired pitch perception or musical memory, or reported changes in music appreciation.

Conclusion

Together with the results of our previous studies of voice recognition, these findings indicate an anterior temporal agnosia syndrome that can include the amnestic variant of prosopagnosia, phonagnosia, and various alterations in music perception, including acquired amusia, reduced musical memory, and altered emotional responses to music.
Dynamic simulations of transcriptional control during cell reprogramming reveal spatial chromatin caging
Authors: Di Stefano Marco , Stadhouders Ralph , Farabella Irene , Castillo David , Serra François , Graf Thomas , Marti-Renom Marc A.
Published: May 2019

Chromosome structure is a crucial regulatory factor for a wide range of nuclear processes. Chromosome Conformation Capture (3C)-based experiments combined with computational modelling are pivotal for unveiling 3D chromosome structure. Here, we introduce TADdyn, a new tool that integrates time-course 3C data, restraint-based modelling, and molecular dynamics to simulate the structural rearrangements of genomic loci in a completely data-driven way. We applied TADdyn onin-situHi-C time-course experiments studying the reprogramming of murine B cells to pluripotent cells, and characterized the structural rearrangements that take place upon changes in the transcriptional state of 11 genomic loci. TADdyn simulations show that structuralcagesform around the transcription starting site of active loci to stabilize their dynamics, by initiating (hit) and maintaining (stick) interactions with regulatory regions. Consistent findings with TADdyn for all loci under study suggest that thishit-and-stickmechanism may represent a general mechanism to trigger and stabilize transcription.
Pregnancy reprograms the enhancer landscape of mammary epithelial cells and alters the response to cMYC-driven oncogenesis
Authors: Feigman Mary J. , Moss Matthew A. , Chen Chen , Cyrill Samantha L. , Ciccone Michael , Frey Wesley D. , Yang Shih Ting , Wilkinson John Erby , dos Santos Camila O.
Published: May 2019

Pregnancy leaves a series of cellular and molecular modifications on mammary epithelial cells (MECs). Pregnancy is also known for decreasing the predisposition of rodent and human MECs to oncogenesis. Here, in order to understand the molecular basis for this effect, we analyzed epigenetic changes in the enhancer landscape of murine post-pregnancy MECs, together with their effect on gene regulation, tissue development and oncogenesis. Using in vivo and in vitro analyses, we found that completion of a pregnancy cycle changed the dynamics of cellular proliferation and gene expression in response to a second pregnancy. Our results also demonstrated that post-pregnancy MECs are resistant to the initial molecular programs driven by cMYC overexpression, a response that blocked MEC proliferation but did not perturb the pregnancy-induced epigenomic landscape. Overall, our findings suggest that pregnancy-induced mammary cancer prevention involves the epigenomic changes in MECs brought about by pregnancy.
Single cell RNA-seq in regenerative and fibrotic biomaterial environments defines new macrophage subsets
Authors: Sommerfeld Sven D. , Cherry Christopher , Schwab Remi M. , Chung Liam , Maestas David R , Laffont Philippe , Stein Julie E. , Tam Ada , Housseau Franck , Taube Janice M. , Pardoll Drew M. , Cahan Patrick , Elisseeff Jennifer H.
Published: May 2019

Macrophages play diverse roles in the immune response to infection, cancer, and wound healing where they respond to local environmental signals, yet identification and phenotypic characterization of functional subsetsin vivoremains limited. We performed single cell RNA sequencing analysis on differentiated macrophages sorted from a biologic matrix-induced regenerative environment versus a synthetic biomaterial foreign body response (FBR), characterized by TH2/interleukin (IL)-4 and TH17/IL-17, respectively. In the regenerative environment, unbiased clustering and pseudotime analysis revealed distinct macrophage subsets responsible for antigen presentation, chemoattraction, and phagocytosis, as well as a small population with expression profiles of both dendritic cells and skeletal muscle. In the FBR environment, we identified a CD9hi+IL-36γ+macrophage subset that expressed TH17-associated molecules characteristic of certain auto-immune responses that were virtually absent in mice lacking the IL-17 receptor. Surface marker combinations including CD9 and CD301b defined macrophage fibrotic and regenerative subsets enabling functional assessment and identification in human tissue. Application of the terminal macrophage subsets to train the SingleCellNet algorithm and comparison to human and mouse macrophages in tumor, lung, and liver suggest broad relevance of macrophage classification. These distinct macrophage subsets demonstrate previously unrecognized myeloid phenotypes involved in different tissue responses and provide new targets for potential therapeutic modulation of certain pathologic states and tissue repair.
Allosteric Inhibition of CRISPR-Cas9 by Bacteriophage-derived Peptides
Authors: Cui Yan-ru , Wang Shao-jie , Chen Jun , Li Jie , Chen Wenzhang , Wang Shuyue , Meng Bing , Zhu Wei , Zhang Zhuhong , Yang Bei , Jiang Biao , Yang Guang , Ma Peixiang , Liu Jia
Published: May 2019

Background

CRISPR-Cas9 has been developed as a therapeutic agent for various infectious and genetic diseases. In many clinically relevant applications, constitutively active CRISPR-Cas9 is delivered into human cells without a temporal control system. Excessive and prolonged expression CRISPR-Cas9 can lead to elevated off-target cleavage. The need for modulating CRISPR-Cas9 activity over the dimensions of time and dose has created the demand of developing CRISPR-Cas off-switches. Protein and small molecule-based CRISPR-Cas inhibitors have been reported in previous studies.

Results

We report the discovery of Cas9-inhibiting peptides from inoviridae bacteriophages. These peptides, derived from the periplasmic domain of phage major coat protein G8P (G8PPD), can inhibit the in vitro activity of Streptococcus pyogenes Cas9 (SpCas9) proteins in an allosteric manner. Importantly, the inhibitory activity of G8PPD on SpCas9 is dependent on the order of guide RNA addition. Ectopic expression of full-length G8P (G8PFL) or G8PPD in human cells can inactivate the genome-editing activity of SpCas9 with minimum alterations of the mutation patterns. Furthermore, unlike the anti-CRISPR protein AcrII4A that completely abolishes the cellular activity of CRISPR-Cas9, G8P co-transfection can reduce the off-target activity of co-transfected SpCas9 while retaining its on-target activity.

Conclusion

G8Ps discovered in the current study represent the first anti-CRISPR peptides that can allosterically inactivate CRISPR-Cas9. This finding may provide insights into developing next-generation CRISPR-Cas inhibitors for precision genome engineering.
Sequence Compression Benchmark (SCB) database — a comprehensive evaluation of reference-free compressors for FASTA-formatted sequences
Authors: Kryukov Kirill , Ueda Mahoko Takahashi , Nakagawa So , Imanishi Tadashi
Published: May 2019

Background

Nearly all molecular sequence databases currently use gzip for data compression. Ongoing rapid accumulation of stored data calls for more efficient compression tool. Although numerous compressors exist, both specialized and general-purpose, choosing one of them was difficult because no comprehensive analysis of their comparative advantages for sequence compression was available.

Findings

We systematically benchmarked 410 settings of 44 compressors (including 26 specialized sequence compressors and 18 general-purpose compressors) on representative FASTA-formatted datasets of DNA, RNA and protein sequences. Each compressor was evaluated on 17 performance measures, including compression strength, as well as time and memory required for compression and decompression. We used 25 test datasets including individual genomes of various sizes, DNA and RNA datasets, and standard protein datasets. We summarized the results as the Sequence Compression Benchmark database (SCB database, http://kirr.dyndns.org/sequence-compression-benchmark/) that allows building custom visualizations for selected subsets of benchmark results.

Conclusion

We found that modern compressors offer large improvement in compactness and speed compared to gzip. Our benchmark allows comparing compressors and their settings using a variety of performance measures, offering the opportunity to select the optimal compressor based on the data type and usage scenario specific to particular application.
Decoupling of inter-regional functional connectivity and regional neural activity in Alzheimer Disease
Authors: Maleki-Balajoo Somayeh , Rahmani Farzaneh , Khosrowabadi Reza , Meng Chun , Grimmer Timo , Drzezga Alexander , Zarei Mojtaba , Sorg Christian , Tahmasian Masoud
Published: May 2019

Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are characterized by aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). It is, however, poorly understood how changes in regional neural activity and inter-regional FC interact in AD and MCI. Here, we investigated the link between regional neural activity and nodal topological measures of FC through simultaneous PET/MR measurement in 20 patients with MCI, 33 patients with AD, and 26 healthy individuals. First, we assessed regional glucose metabolism identified through FDG-PET (rFDG) (as a proxy of regional neural activity), and regional FC topology through clustering coefficient (CC) and degree centrality (DC) (as surrogates of local segregation and global connectivity, respectively). Next, we examined the potential moderating effect of disease status (AD or MCI) on the link between rFDG and FC topology using hierarchical moderated multiple regression analysis. Alterations in rFDG, CC, and DC were widespread in patients, and AD alters physiological coupling between regional metabolism and functional connectivity particularly in the inferior temporal gyus and supplementary motor areas. While rFDG correlated with CC in healthy subjects, this correlation was lost in AD patients. We suggest that AD pathology decouples the normal association between regional neural activity and functional segregation.
Generation of strong casein kinase 1 inhibitor of Arabidopsis thaliana
Authors: Saito Ami N , Matsuo Hiromi , Kuwata Keiko , Ono Azusa , Kinoshita Toshinori , Yamaguchi Junichiro , Nakamichi Norihito
Published: May 2019

Casein kinase 1 (CK1) is an evolutionarily conserved protein kinase among eukaryotes. Studies on yeast, fungi, and animals have revealed that CK1 plays roles in divergent biological processes. By contrast, the collective knowledge regarding the biological roles of plant CK1 lags was behind those of animal CK1. One of reasons for this is that plants have more multiple genes encoding CK1 than animals. To accelerate the research for plant CK1, a strong CK1 inhibitor that efficiently inhibits multiple members of CK1 proteins in vivo (in planta) is required. Here, we report a novel strong CK1 inhibitor of Arabidopsis (AMI-331). Using a circadian period-lengthening activity as estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship (SAR) study of PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride), a potent CK1 inhibitor of Arabidopsis, and found that PHA767491 analogues bearing a propargyl group at the pyrrole nitrogen atom (AMI-212) or a bromine atom at the pyrrole C3 position (AMI-23) enhance the period-lengthening activity. The period lengthening activity of a hybrid molecule of AMI-212 and AMI-23 (AMI-331) is about 100-fold stronger than that of PHA767491. An in vitro assay indicated a strong inhibitory activity of CK1 kinase by AMI-331. Also, affinity proteomics using an AMI-331 probe showed that targets of AMI-331 are mostly CK1 proteins. As such, AMI-331 is a strong potent CK1 inhibitor that shows promise in the research of CK1 in plants.
Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma
Authors: Yazdanifar Mahboubeh , Zhou Ru , Grover Priyanka , Williams Chandra , Bose Mukulika , Moore Laura Jeffords , Wu Shu-ta , Chi Richard , Maher John , Dreau Didier , Mukherjee Pinku
Published: May 2019

Chimeric antigen receptor engineered T cells (CAR T cells) have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumorsin vivo.PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease.
A general LC/MS-based RNA sequencing method for direct analysis of multiple-base modifications in RNA mixtures
Authors: Zhang Ning , Shi Shundi , Jia Tony Z. , Ziegler Ashley , Yoo Barney , Yuan Xiaohong , Li Wenjia , Zhang Shenglong
Published: May 2019

A complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and noncanonical bases; this in turn requires advances in current sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these nonstandard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via integration of a hydrophobic end-labeling strategy with of 2-D mass-retention time LC/MS analysis to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA vs. its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site of the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification types and can also be used in the quality control of modified therapeutic RNAs.
Jasmonate-regulated ERF109-MYB51-MYC3 ternary complexes control indolic glucosinolates biosynthesis
Authors: Zhang kaixuan , Meng Yu , Li Jinbo , Ding Mengqi , Khurshid Muhammad , Li Qiong , Lu Xiaoling , Zhou Meiliang
Published: May 2019

Jasmonates (JAs) are plant hormones which regulate biosynthesis of many secondary metabolites, such as glucosinolates (GLSs), through JAs-responsive transcription factors (TFs). The JAs-responsiveCYP83B1gene, has been shown to catalyze the conversion of indole-3-acetaldoxime (IAOx) to indolic glucosinolates (IGLSs). However, little is known about the regulatory mechanism ofCYP83B1gene expression by JAs. In yeast one-hybrid screens using theCYP83B1promoter as bait we isolated two JAs-responsive TFs ERF109 and MYB51 that are involved in JAs-regulated IGLS biosynthesis. Furthermore, using a yeast two-hybrid assay, we identified ERF109 as an interacting partner of MYB51, and Jasmonate ZIM-domain (JAZ) proteins as interactors of MYB51, and BTB/POZ-MATH (BPM) proteins as interactors of ERF109. Both JAZ and BPM proteins are necessary for the full repression of the ERF109-MYB51-MYC3 ternary complex activity onCYP83B1gene expression and JA-regulated IGLS biosynthesis. Biochemical analysis showed that the 26S proteasome-mediated degradation of ERF109 protein is mediated by a CRL3BPME3 ligase independently of JA signaling. Genetic and physiological evidence shows that MYB51 acts as an adaptor and activator to bridge the interaction with the co-activators MYC3 and ERF109, for synergistically activating theCYP83B1gene expression, and all three factors are essential and exert a coordinated control in JAs-induced IGLS biosynthesis. Overall, this study provides insights into the molecular mechanisms of JAs-responsive ERF109-MYB51-MYC3 ternary complexes in controlling JAs-regulated GLSs biosynthesis, which provides a better understanding of plant secondary metabolism.

One-sentence summary

The JA-responsive ERF109-MYB51-MYC3 ternary complex controls JAs-regulated GLSs biosynthesis.
AI’s path to the present and the painful transitions along the way
Authors: Garcia-Murillo Martha , MacInnes Ian
Published: May 2019

Purpose

Artificial intelligence (AI) is likely to have a significant impact on work. It will enhance, but also displace, some professions. This paper aims to look retrospectively at the impact that previous revolutionary computing technologies have had and the institutional values that have shaped the way workers were affected.

Design/methodology/approach

This historical investigation relies on academic, government and trade publications of earlier periods in the development of computer technology. The analysis relies on the literature on institutional economics to understand societal outcomes. Within this framework, this paper explores both the ceremonial values associated with tradition and the instrumental values associated with the pursuit of knowledge.

Findings

The AI revolution, like previous technological evolutions, will go through stages. Initial implementations will suffer from failures that will, however, generate employment; but, as the technology improves, the AI revolution is likely to enhance productivity but displace workers. Up to this point, the US Government has not been able to respond adequately to the challenge. This paper attributes this to the ceremonial values that public officials and society entertain about personal responsibility and small government.

Practical implications

Given the differences in values, this study recommends fending off negative effects though education but also experimenting with other solutions at the local level.

Originality/value

Through the lens of history, this study provides a glimpse of what may happen. It also provides a framework that helps understand the outcomes of earlier technological revolutions.
On the theoretical basis of memory-free approaches for fractional differential equations
Authors: Liu Q.X. , Liu J.K. , Chen Y.M.
Published: May 2019

Purpose

A nonclassical method, usually called memory-free approach, has shown promising potential to release arithmetic complexity and meets high memory-storage requirements in solving fractional differential equations. Though many successful applications indicate the validity and effectiveness of memory-free methods, it has been much less understood in the rigorous theoretical basis. This study aims to focus on the theoretical basis of the memory-free Yuan–Agrawal (YA) method [Journal of Vibration and Acoustics 124 (2002), pp. 321-324].

Design/methodology/approach

Mathematically, the YA method is based on the validity of two fundamental procedures. The first is to reverse the integration order of an improper quadrature deduced from the Caputo-type fractional derivative. And, the second concerns the passage to the limit under the integral sign of the improper quadrature.

Findings

Though it suffices to verify the integration order reversibility, the uniform convergence of the improper integral is proved to be false. Alternatively, this paper proves that the integration order can still be reversed, as the target solution can be expanded as Taylor series on [0, ∞). Once the integration order is reversed, the paper presents a sufficient condition for the passage to the limit under the integral sign such that the target solution is continuous on [0, ∞). Both positive and counter examples are presented to illustrate and validate the theoretical analysis results.

Originality/value

This study presents some useful results for the real performance for the YA and some similar memory-free approaches. In addition, it opens a theoretical question on sufficient and necessary conditions, if any, for the validity of memory-free approaches.