bluuebunny/crossref_metadata_2025 huggingface dataset:
Dysphagia in Myositis
Authors: Azola Alba , Mulheren Rachel , Mckeon Genevieve , Lloyd Thomas , Christopher-Stine Lisa , Palmer Jeffrey , Chung Tae Hwan
Published: November 2019

Objectives

Dysphagia in patients with myositis is associated with an increased risk of aspiration pneumonia. However, the pathophysiology of dysphagia is poorly understood. The aim of this study was to understand how myositis affects swallowing physiology on videofluoroscopic swallow study.

Design

This is a retrospective review of video fluoroscopic swallowing studies on 23 myositis patients with dysphagia from 2011 to 2016. Swallow studies were analyzed by timing of swallowing events and duration of swallowing events, diameter of upper esophageal sphincter opening, Modified Barium Swallow Impairment Profile, and Penetration-Aspiration Scale. The outcome measures for patients were compared with an archived videofluoroscopic swallow study from healthy, age-matched participants by Wilcoxon rank-sum tests.

Results

Patients with myositis had a shorter duration of upper esophageal sphincter opening (P < 0.0001) and laryngeal vestibule closure (P < 0.0001) than healthy subjects. The diameter of upper esophageal sphincter opening did not differ between groups. Patients with myositis presented with higher scores on the MBSIMP than healthy subjects, indicating great impairment particularly during the pharyngeal phase of swallowing, and a higher frequency of penetration and aspiration.

Conclusions

Dysphagia in patients with myositis may be attributed to reduced endurance of swallowing musculature rather than mechanical obstruction of the upper esophageal sphincter.
Chimeric Antigen Receptor T Cells in Chronic Lymphocytic Leukemia
Authors: Rhodes Joanna M. , Schuster Stephen J.
Published: November 2019

Recent advances in the treatment of chronic lymphocytic leukemia (CLL) have dramatically changed outcomes for patients. Despite these improvements, CLL is still considered incurable. Chimeric antigen receptor–modified T cells have demonstrated the ability to produce long-term remissions in subsets of heavily pretreated patients with B-cell malignancies, including CLL. Unfortunately, the majority of patients with CLL do not attain durable responses. Recent studies have focused on understanding the mechanisms and predictors of response in these patients. In this review, we will discuss the literature for chimeric antigen receptor–modified T-cell therapy in CLL and highlight mechanisms of response and resistance as currently understood.
Phosphatidylinositol 3 Kinase δ Inhibitors
Authors: Brown Jennifer R.
Published: November 2019

Inhibitors of PI3Kδ hold great potential for the therapy of chronic lymphocytic leukemia and B-cell malignancies. After initially exciting efficacy results with idelalisib, the first-in-class inhibitor, the emergence of unexpected and unpredictable autoimmune toxicities, worse in less heavily treated and younger patients, has decreased the use of the currently available inhibitors. Newer drugs in development are attempting to reduce toxicity with novel schedules and/or combinations. This article reviews the clinical data on efficacy and toxicity across the class and discusses ongoing efforts to understand and mitigate the likely on-target autoimmune toxicity.
How Patient Decision-Making Characteristics Affect Satisfaction in Facial Plastic Surgery: A Prospective Pilot Study
Authors: Oliver Jeremie D. , Menapace Deanna C. , Staab Jeffrey P. , Friedman Oren , Recker Chelsey , Hamilton Grant S.
Published: November 2019

Background:

The main objective of this study was to prospectively analyze which personality traits, clinical psychiatric states, and patient decision-making characteristics predict who will be less satisfied after facial plastic surgery.

Methods:

This prospective study enrolled 60 adult subjects into one of three groups: aesthetic, functional, and reconstructive facial plastic surgery procedures (n = 20 in each group) from November of 2011 to February of 2016. Self-report surveys of personality traits (i.e., NEO Personality Inventory-Revised), psychiatric state (i.e., Patient Health Questionnaire, Generalized Anxiety Disorder, Health Anxiety Inventory–Short Form), and decision-making characteristics (maximizer/satisficer survey) were given during the preoperative clinic visits. In postoperative follow-up, satisfaction questionnaires at 3, 6, and 12 months were administered. Data analysis examined associations between patient satisfaction, decision-making characteristics, and psychiatric variables.

Results:

Bivariate analyses showed that maximizer/satisficer decision-making style was significantly related to patient satisfaction scores in the year following surgery. This difference reached statistical significance at 6 months and remained a strong trend at 12 months. Patients who were less than extremely satisfied at both postoperative time points were more likely to portray the maximizer decision-making style. No other variables were associated with patient satisfaction at any time point. Maximizer/satisficer survey scores were not associated with self-reports of depression, anxiety, or illness anxiety. Mean scores on the maximizer/satisficer survey did not differ among the aesthetic, functional, and reconstructive groups.

Conclusions:

The maximizer/satisficer survey captures an aspect of patient care not traditionally measured by standard clinical psychometric screening tools to help predict satisfaction. A short questionnaire targeting consumer decision-making may be a helpful tool for preoperative counseling.
Resident Working Hour Restrictions Increased the Workload of the Medical Emergency Team: A Retrospective Observational Study
Authors: Moon Kyoung Min , Huh Jin Won , Park Shinhee , Hong Sang-Bum , Lim Chae-Man , Koh Younsuck
Published: November 2019

Background

Restrictions to residents' working hours have been shown to increase the workload of other medical resources; few studies have measured the effects on medical emergency teams (METs).

Objectives

This study evaluated how limiting residents' working hours affected the workload of MET in a pulmonology unit.

Methods

This retrospective observational study analyzed MET activity during periods before and after we limited the working hours of residents in our pulmonary unit to 88 h/wk: Period 1, March 2014 to February 2015; and Period 2, March 2015 to February 2016. Medical emergency team activities, dose (activations/1000 admissions), intensive care unit transfers, and mortality were compared between the two periods for weekdays and for weekends and holidays.

Results

There were no significant differences between the two periods in MET dose (85.0 in Period 1 versus 91.3 in Period 2, P = 0.675), intensive care unit transfers (P = 0.828), 30-day mortality (P = 0.701), and 60-day mortality (P = 0.531). However, some activities increased significantly or near significantly in Period 2, including portable echocardiography (P < 0.001), arterial line insertion (P = 0.034), mechanical ventilation (P = 0.063), and fluid therapy (P = 0.220). These increases were greater for weekends and holidays than for weekdays.

Conclusions

Since December 2017, a specific law for improving the training environment and status of residents has been implemented and applied at all hospitals in Korea. This legal restriction to working hours raises concerns regarding other medical personnel and system improvements to ensure patient safety and care continuity.
HIV-Related Implementation Research for Key Populations: Designing for Individuals, Evaluating Across Populations, and Integrating Context
Authors: Schwartz Sheree R. , Rao Amrita , Rucinski Katherine B. , Lyons Carrie , Viswasam Nikita , Comins Carly A. , Olawore Oluwasolape , Baral Stefan
Published: November 2019

Introduction:

Key populations, including men who have sex with men, transgender people, sex workers, people who inject drugs, and incarcerated populations, experience high burdens of HIV and urgently need effective interventions. Yet the evidence base for implementation research (IR) with key populations remains weak and poses specific challenges to epidemiologic inference. We apply the Consolidated Framework for IR to consider specific challenges and recommendations for IR with key populations.

Discussion:

Individuals within key populations exist within inner and outer settings—including organizational structures, legal (eg, criminalization), and funding environments—which influence the design, adoption and fidelity of interventions, and the potential sustainability of intervention scale-up. Underlying vulnerabilities and external stressors experienced at the individual level (eg, homelessness, violence) further impact participation and retention in IR. Thus, researchers should account for representation in the research process, beginning with community engagement in IR design and consideration of enumeration/sampling methods for key populations who lack probabilistic sampling frames. Interventions for key populations require substantial adaptation and complexity (eg, individually tailored, multicomponent) to ensure appropriateness; however, there is tension between the need for complexity and challenges to internal validity (fidelity) and external validity (generalizable scale-up). Finally, integrating contextual, sampling, and implementation elements into analytic approaches is critical for effectiveness evaluation.

Conclusions:

Translation of efficacious findings at the individual level to effectiveness at the population level requires recognition of risk heterogeneity. Recognizing the nuances of working with key populations is essential to ensure that individuals are represented by design and therefore gains in population health can be achieved.
Using Social Networks to Understand and Overcome Implementation Barriers in the Global HIV Response
Authors: Harling Guy , Tsai Alexander C.
Published: November 2019

Background:

Despite the development of several efficacious HIV prevention and treatment methods in the past 2 decades, HIV continues to spread globally. Uptake of interventions is nonrandomly distributed across populations. Such inequality is socially patterned and reinforced by homophily arising from both social selection (becoming friends with similar people) and influence (becoming similar to friends).

Methods:

We conducted a narrative review to describe how social network analysis methods—including egocentric, sociocentric, and respondent-driven sampling designs—provide tools to measure key populations, to understand how epidemics spread, and to evaluate intervention take-up.

Results:

Social network analysis–informed designs can improve intervention effectiveness by reaching otherwise inaccessible populations. They can also improve intervention efficiency by maximizing spillovers, through social ties, to at-risk but susceptible individuals. Social network analysis–informed designs thus have the potential to be both more effective and less unequal in their effects, compared with social network analysis–naïve approaches. Although social network analysis-informed designs are often resource-intensive, we believe they provide unique insights that can help reach those most in need of HIV prevention and treatment interventions.

Conclusion:

Increased collection of social network data during both research and implementation work would provide important information to improve the roll-out of existing studies in the present and to inform the design of more data-efficient, social network analysis–informed interventions in the future. Doing so will improve the reach of interventions, especially to key populations, and to maximize intervention impact once delivered.
Data for Care (D4C) Alabama: Clinic-Wide Risk Stratification With Enhanced Personal Contacts for Retention in HIV Care via the Alabama Quality Management Group
Authors: Sohail Maira , Rastegar Jeremiah , Long Dustin , Rana Aadia , Levitan Emily B. , Reed-Pickens Harriette , Batey David Scott , Ross-Davis Kelly , Gaddis Kathy , Tarrant Ashley , Parmar Jitesh , Raper James L. , Mugavero Michael J.
Published: November 2019

Background:

The Alabama Quality Management Group (AQMG), a consortium of 9 Ryan White–funded part C and D clinics, distributed statewide was established in 2006 under the guidance from the Health and Resources Services Administration with a clinical quality improvement (CQI) focus.

Methods:

We describe the origins and evolution of the AQMG, including requisite shifts from aggregate clinic-wide to de-identified individual-level data reporting for implementation of the Data for Care (D4C-AL) Alabama program. The D4C-AL strategy uses a clinic-wide risk stratification of all patients based on missed clinic visits in the previous 12 months. Intermediate (1–2 missed visits) and high-risk patients (>3 missed visits) receive the evidence-informed Retention through Enhanced Personal Contact intervention. We report on a pilot of the D4CAL program in 4 of 33 primary HIV care clinics at the UAB 1917 Clinic.

Results:

Among 3859 patients seen between April 2018 and February 2019, the missed visit rate was not significantly different between the D4C-1917 (19.2%) and non-D4C clinics (20.5%) in a preintervention period (May 2017–April 2018). However, a significantly lower missed visit rate was observed in the D4C-1917 vs. non–D4C-1917 clinics during the intervention period (April 2018–February 2019, P = 0.049).

Conclusions:

The AQMG has been transformed into a health service research and implementation science platform, building on a shared vision, mission, data reporting, and quality improvement focus. Moreover, CQI may be viewed as an implementation strategy that seeks to enhance uptake and sustained use of effective interventions with D4C-AL representing a prototype for future initiatives embedded within extant quality improvement consortia.
Seeing Is Believing? Unique Capabilities of Internet-Only Studies as a Tool for Implementation Research on HIV Prevention for Men Who Have Sex With Men: A Review of Studies and Methodological Considerations
Authors: Grov Christian , Westmoreland Drew , Rendina H. Jonathon , Nash Denis
Published: November 2019

Background:

In 2014, Grov et al published a comprehensive review cataloguing both men who have sex with men's (MSM's) sexual behavior transitions in online environments from the 1990s through 2013, as well as researchers' efforts in tandem to use the internet to engage MSM into research, treatment, and prevention.

Methods:

In this article, we discuss historical events and research having occurred in the half decadesincethe Grov et al publication.

Results:

Notable transitions include MSM's expanded use of geosocial networking apps, as well as other forms of social media accessed primarily through mobile devices, as well as the addition ofbiomedicalprevention strategies (eg, pre-exposure prophylaxis and undetectable = untransmittable) to the proverbial HIV prevention toolkit. In tandem, researchers have rapidly expanded their employment of internet-mediated methods for the recruitment and engagement of key populations for HIV research, treatment, and prevention. In this article, we discuss methodological considerations for using the internet to conduct HIV prevention research with MSM: (1) sources of recruitment (eg, geosocial apps, Facebook, crowdsourced online panels); (2) design (eg, cross sectional, longitudinal, diaries); (3) incentives (including disincentivizing fraudulent participants and/or spam bots); (4) confidentiality; and (5) representativeness.

Conclusion:

We conclude by discussing future directions in HIV prevention research in light of forthcoming technologies such as fifth generation (5G) mobile networks, combined use of self-collected biological data alongside self-report, and the utility of metadata and metaresearch to document, evaluate, and inform best practices.
Comparison of Three-Dimensional Printing and Computer-aided Engineering in Presurgical Volumetric Assessment of Bilateral Alveolar Clefts
Authors: Chen Shuxiu , Liu Bing , Liu Jing , Yin Ningbei , Wang Yongqian
Published: November 2019

This study aimed to evaluate 2 advanced methods for presurgical calculation of bilateral alveolar cleft defect volume using 3-dimensional (3D) printing and computer-aided engineering (CAE) software. Twelve patients with bilateral alveolar cleft (4 females, 8 males, age range 8–11 years) were enrolled in the study. All patients underwent preoperative helical computed tomography scans, and the digital imaging and communications in medicine (DICOM) data of the computed tomography images were analyzed using 3D printing and CAE software. The 3D-printed model used a simulated graft, and graft volume was measured by water displacement. The CAE software used a subtractive method to calculate volume. Simulated graft volumes and CAE-software-derived volumes were compared using Pearson's correlation test and paired Student's t-test. The average volume of the simulated bone grafts obtained using 3D-printed models was 1.45 mL, which was lower than the CAE-software-derived mean volume of 1.52 mL. The mean calculation time using the 3D-printed model was 51.5 minutes, which was 32.1 minutes longer than the average 19.4 minutes when using CAE software. Paired Student's t-test revealed no statistically significant difference between the volumes derived from these methods. The results of this study further validated the use of 3D printing and CAE technique in bilateral alveolar defect repair. The CAE software is more cost-effective in presurgical volumetric assessment. Moreover, 3D models overcome limitations of 3D visualizations by providing tactile feedback and superior appreciation of visuospatial relationships among anatomical structures.
Primary Cleft Rhinoplasty: Surgical Outcomes and Complications Using Three Techniques for Unilateral Cleft Lip Nose Repair
Authors: Rossell-Perry Percy
Published: November 2019

Background:

This study represents a single surgeon's 10 years of experience addressing unilateral cleft lip and palate nose deformity. The purpose was to compare surgical outcomes and related complications using 3 different techniques to improve nasal shape in primary unilateral cleft rhinoplasty.

Methods:

This retrospective study with Institutional Ethical Committee approval compares 3 groups of patients with unilateral cleft lip nose and palate who were operated on using different techniques from 2007 to 2017. Surgical outcomes were analyzed by physical examination at least 1 year after primary rhinoplasty. Anthropometric measurements were obtained for the cleft and noncleft sides of the nose.

Results:

Approach with general analysis indicated differences among the 3 techniques. The author's comparative study revealed differences in nose symmetry and related complications, including increased recurrence of nose deformity using the modified McComb technique. Better short-term nose symmetry was observed using Potter technique and the V-Y-Z rhinoplasty.

Conclusions:

Potter approach and the V-Y-Z techniques achieve better short-term nose symmetry than the McComb method. Complications were less common in the group of patients operated on using the modified McComb technique. Additional studies are required to evaluate functional and long-term outcomes after primary rhinoplasty using the proposed methods.
The Influence of Epigenetic Factors in Four Pairs of Twins With Non-Syndromic Craniosynostosis
Authors: Farooq Saadia , Morton Jenny , Lloyd Mark , Krishna Sandhya Trichinopoly
Published: November 2019

The aims of this retrospective case series were to investigate whether twins born with craniosynostosis mirrored each other regarding operative surgery performed, age of undertaking surgery; outcomes in speech, language, and developmental milestones and what environmental factors were present for each set of twins.

Case selection was based on clinical and radiographical evidence of craniosynostosis amongst twin sets. The twin sets included were those with craniosynostosis who had different sutures affected or those with the same suture affected but with a varying degree of severity.

The presence of the following factors may have played an influential role in the clinical presentation of the twins; these were as follows: a maternal history of smoking, breech presentation, and genetic mutations. It was notable that the overall outcomes for the twins in this study were similar.

These cases highlight the multifactorial nature in the development of craniosynostosis and how this influenced the phenotypic presentation of the twins.
National Database Reported Outcomes Following Craniosynostosis Reconstruction
Authors: Massenburg Benjamin B. , Nassar Amer H. , Hopper Richard A.
Published: November 2019

Background:

While there has been ample interest and literature published regarding craniosynostosis surgical technique, there are few reports on adverse hospital and health system outcomes. The purpose of this study was to describe rate of and risk factors for complications, and adverse outcomes following craniosynostosis reconstruction.

Methods:

This study retrospectively reviewed the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) Pediatric database and identified all patients undergoing craniosynostosis repair from 2012 to 2016. Univariate logistic regression analysis was used to identify significant associations between preoperative risk factors and adverse outcomes. Multivariate logistic regression analysis was then used to identify independent risk factors and causes of prolonged operative times, transfusions, reoperation, prolonged length of hospital stays, and readmission.

Results:

There were 3924 patients included who underwent craniosynostosis repair, of whom 1732 underwent frontoorbital advancement and 2192 underwent cranial vault remodeling. Transfusion was the most common NSQIP reportable outcome, occurring for 66.5% of all patients. The incidence of reoperation was 2.4% and readmission was 3.0%.

Conclusion:

This study provides a large descriptive analysis of craniosynostosis repair throughout the United States. Largely nonmodifiable patient risk factors lead to worse health system metrics, with young age, gastrointestinal comorbidities, American Society of Anesthesiologist scores of 3 and greater, reoperation, and a prolonged length of stay as independent risk factors for readmission. This analysis can be used to identify the standard of practice in synostosis care and enhance the implementation of ancillary care services to provide safe and cost-effective care for patients undergoing craniosynostosis repair.
The Consequences of Aging On the Response to Injury and Critical Illness
Authors: Joseph Bellal , Scalea Thomas
Published: November 2019

Changing demographic trends have led to an increase in the overall geriatric trauma patient volume. Furthermore, the intersection of aging and injury can be problematic because geriatric patients have multiple comorbidities, geriatric-specific syndromes, and reduced physiological reserve. Despite mounting evidence that frail geriatric patients have inferior outcomes following trauma, very few studies have examined the effect of aging on the biological response to injury. In the present article, we review the current literature and explore the pathophysiological rationale underlying observed data, available evidence, and future directions on this topic.
Influence of Different Partial Pressures of Oxygen During Continuous Hypothermic Machine Perfusion in a Pig Kidney Ischemia-reperfusion Autotransplant Model
Authors: Darius Tom , Vergauwen Martial , Smith Thomas B. , Patel Kamlesh , Craps Julie , Joris Virginie , Aydin Selda , Ury Benoît , Buemi Antoine , De Meyer Martine , Nath Jay , Ludwig Christian , Dessy Chantal , Many Marie-Christine , Gianello Pierre , Mourad Michel
Published: November 2019

Background.

The optimal perfusate partial pressure of oxygen (Po
2) during hypothermic machine perfusion (HMP) is unknown. The aims of the study were to determine the functional, metabolic, structural, and flow dynamic effects of low and high perfusate Po
2 during continuous HMP in a pig kidney ischemia-reperfusion autotransplant model.

Methods.

The left kidneys of a ±40 kg pigs were exposed to 30 minutes of warm ischemia and randomized to receive 22-hour HMP with either low perfusate Po
2 (30% oxygen, low oxygenated HMP [HMPO2]) (n = 8) or high perfusate Po
2 (90% oxygen, HMPO2high) (n = 8), before autotransplantation. Kidneys stored in 22-hour standard HMP (n = 6) and 22-hour static cold storage (n = 6) conditions served as controls. The follow-up after autotransplantation was 13 days.

Results.

High Po
2 resulted in a 3- and 10-fold increase in perfusate Po
2 compared with low HMPO2 and standard HMP, respectively. Both HMPO2 groups were associated with superior graft recovery compared with the control groups. Oxygenation was associated with a more rapid and sustained decrease in renal resistance. While there was no difference in functional outcomes between both HMPO2 groups, there were clear metabolic differences with an inverse correlation between oxygen provision and the concentration of major central metabolites in the perfusion fluid but no differences were observed by oxidative stress and metabolic evaluation on preimplantation biopsies.

Conclusions.

While this animal study does not demonstrate any advantages for early graft function for high perfusate Po
2, compared with low perfusate Po
2, perfusate metabolic profile analysis suggests that aerobic mechanism is better supported under high perfusate Po
2 conditions.
Phylodynamics of pertussis in the vaccine era: transition to re-emergence
Authors: Bento Ana I. , Taujale Rahil , Schot Corrie , Bosch Thijs , Mariman Rob , King Aaron A. , Rohani Pejman
Published: November 2019

This manuscript has been withdrawn owing to an author dispute.
Discovery of 318 novel loci for type-2 diabetes and related micro- and macrovascular outcomes among 1.4 million participants in a multi-ethnic meta-analysis
Authors: Vujkovic Marijana , Keaton Jacob M. , Lynch Julie A. , Miller Donald R. , Zhou Jin , Tcheandjieu Catherine , Huffman Jennifer E. , Assimes Themistocles L. , Judy Renae L. , Huang Jie , Lee Kyung Min , Klarin Derek , Pyarajan Saiju , Danesh John , Melander Olle , Rasheed Asif , Qamar Nadeem , Sheikh Saqib S. , Hameed Shahid , Qureshi Irshad H. , Afzal Muhammad N. , Jahazaib Uzma , Jalal Anjum , Abbas Shahid , Sheng Xin , Gao Long , Kaestner Klaus H. , Susztak Katalin , Sun Yan V. , Duvall Scott L. , Cho Kelly , Lee Jennifer S. , Gaziano John M. , Philips Lawrence S. , Meigs James B. , Reaven Peter D. , Wilson Peter W. , Edwards Todd L. , Rader Daniel J. , Damrauer Scott M. , O’Donnell Christopher J. , Tsao Philip S. ,   HPAP Consortium, Regeneron Genetics Center, VA Million Veteran Program, Chang Kyong-Mi , Voight Benjamin F. , Saleheen Danish
Published: November 2019

We investigated type 2 diabetes (T2D) genetic susceptibility in a multi-ethnic meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP) and other biobanks. We identified 558 autosomal and 10 X-chromosome T2D-associated variants, of which 286 autosomal and 7 X-chromosome variants were previously unreported. Ancestry-specific analyses identified 25 additional novel T2D-susceptibility variants. Transcriptome-wide association analysis detected 3,568 T2D-associations with T2D-colocalized genetically predicted gene expression of 804 genes in 52 tissues, of which 687 are novel. Fifty-four of these genes are known to interact with FDA-approved drugs and chemical compounds. T2D polygenic risk score was strongly associated with increased the risk of T2D-related retinopathy, and additionally showed evidence for association with chronic kidney disease (CKD), neuropathy, and peripheral artery disease (PAD). We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including 3 for coronary heart disease, 1 for PAD, 2 for stroke, 4 for retinopathy, 2 for CKD, and 1 for neuropathy. Our findings may identify potential novel therapeutic targets for T2D and genomic pathways that link T2D and its vascular outcomes.
Structural modularity of the XIST ribonucleoprotein complex
Authors: Lu Zhipeng , Guo Jimmy K. , Wei Yuning , Dou Diana R. , Zarnegar Brian , Ma Qing , Li Rui , Zhao Yang , Liu Fan , Choudhry Hani , Khavari Paul A. , Chang Howard Y.
Published: November 2019

Long noncoding RNAs are thought to regulate gene expression by organizing protein complexes through unclear mechanisms. XIST controls the inactivation of an entire X chromosome in female placental mammals. Here we develop and integrate several orthogonal structure-interaction methods to demonstrate that XIST RNA-protein complex folds into an evolutionarily conserved modular architecture. Chimeric RNAs and clustered protein binding in fRIP and eCLIP experiments align with long-range RNA secondary structure, revealing discrete XIST domains that interact with distinct sets of effector proteins. CRISPR-Cas9-mediated permutation of the Xist A-repeat location shows that A-repeat serves as a nucleation center for multiple Xist-associated proteins and m6A modification. Thus modular architecture plays an essential role, in addition to sequence motifs, in determining the specificity of RBP binding and m6A modification. Together, this work builds a comprehensive structure-function model for the XIST RNA-protein complex, and suggests a general strategy for mechanistic studies of large ribonucleoprotein assemblies.
Neglecting model selection alters phylogenetic inference
Authors: Gerth Michael
Published: November 2019

Molecular phylogenetics is a standard tool in modern biology that informs the evolutionary history of genes, organisms, and traits, and as such is important in a wide range of disciplines from medicine to palaeontology. Maximum likelihood phylogenetic reconstruction involves assumptions about the evolutionary processes that underlie the dataset to be analysed. These assumptions must be specified in forms of an evolutionary model, and a number of criteria may be used to identify the best-fitting from a plethora of available models of DNA evolution. Using many empirical and simulated nucleotide sequence alignments, Abadi et al.1 have recently found that phylogenetic inferences using best models identified by six different model selection criteria are, on average, very similar to each other. They further claimed that using the model GTR+I+G4 without prior model-fitting results in similarly accurate phylogenetic estimates, and consequently that skipping model selection entirely has no negative impact on many phylogenetic applications. Focussing on this claim, I here revisit and re-analyse some of the data put forward by Abadi et al. I argue that while the presented analyses are sound, the results are misrepresented and in fact - in line with previous work - demonstrate that model selection consistently leads to different phylogenetic estimates compared with using fixed models.
Single cell RNA sequencing of calvarial and long bone endocortical cells
Authors: Ayturk Ugur M. , Scollan Joseph P. , Vesprey Alexander , Jacobsen Christina M. , Pajevic Paola Divieti , Warman Matthew L.
Published: November 2019

Single cell RNA-seq (scRNA-seq) is emerging as a powerful technology to examine transcriptomes of individual cells. We determined whether scRNA-seq could be used to detect the effect of environmental and pharmacologic perturbations on osteoblasts. We began with a commonly used in vitro system in which freshly isolated neonatal mouse calvarial cells are expanded and induced to produce a mineralized matrix. We used scRNA-seq to compare the relative cell type abundances and the transcriptomes of freshly isolated cells to those that had been cultured for 12 days in vitro. We observed that the percentage of macrophage-like cells increased from 6% in freshly isolated calvarial cells to 34% in cultured cells. We also found that Bglap transcripts were abundant in freshly isolated osteoblasts but nearly undetectable in the cultured calvarial cells. Thus, scRNA-seq revealed significant differences between heterogeneity of cells in vivo and in vitro. We next performed scRNA-seq on freshly recovered long bone endocortical cells from mice that received either vehicle or Sclerostin-neutralizing antibody for 1 week. Bone anabolism-associated transcripts were also not significantly increased in immature and mature osteoblasts recovered from Sclerostin-neutralizing antibody treated mice; this is likely a consequence of being underpowered to detect modest changes in gene expression, since only 7% of the sequenced endocortical cells were osteoblasts, and a limited portion of their transcriptomes were sampled. We conclude that scRNA-seq can detect changes in cell abundance, identity, and gene expression in skeletally derived cells. In order to detect modest changes in osteoblast gene expression at the single cell level in the appendicular skeleton, larger numbers of osteoblasts from endocortical bone are required.
The direction of associations: prior knowledge promotes hippocampal separation, but cortical assimilation
Authors: Bein Oded , Reggev Niv , Maril Anat
Published: November 2019

What does it mean to say, “a new association is learned”? And how is this learning different when adding new information to already-existing knowledge? Here, participants associated pairs of faces while undergoing fMRI, under two different conditions: a famous, highly-familiar face with a novel face or two novel faces. We examined multivoxel activity patterns corresponding to individual faces before and after learning. In the hippocampus, paired novel faces became more similar to one another through learning. In striking contrast, members of famous-novel pairs became distinct. In the cortex, prior knowledge led to integration, but in a specific direction: the representation of the novel face became similar to that of the famous face before learning, but less so vice versa, suggesting assimilation of new into old memories. We propose that hippocampal separation might resolve interference between existing and newly learned information, allowing cortical assimilation. Associations are formed through divergent but specific neural codes, that are adaptively shaped by the internal state of the system – its prior knowledge.
Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data
Authors: Rafehi Haloom , Szmulewicz David J. , Pope Kate , Wallis Mathew , Christodoulou John , White Susan M , Delatycki Martin B , Lockhart Paul J , Bahlo Melanie
Published: November 2019

Background

Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible.

Objectives

To determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance.

Methods and Results

WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis (<five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56.

Conclusions

the that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of individuals with a clinical diagnosis of ataxia.
MetaEuk – sensitive, high-throughput gene discovery and annotation for large-scale eukaryotic metagenomics
Authors: Karin Eli Levy , Mirdita Milot , Söding Johannes
Published: November 2019

Background

Metagenomics is revolutionizing the study of microorganisms and their involvement in biological, biomedical, and geochemical processes, allowing us to investigate by direct sequencing a tremendous diversity of organisms without the need for prior cultivation. Unicellular eukaryotes play essential roles in most microbial communities as chief predators, decomposers, phototrophs, bacterial hosts, symbionts and parasites to plants and animals. Investigating their roles is therefore of great interest to ecology, biotechnology, human health, and evolution. However, the generally lower sequencing coverage, their more complex gene and genome architectures, and a lack of eukaryote-specific experimental and computational procedures have kept them on the sidelines of metagenomics.

Results

MetaEuk is a toolkit for high-throughput, reference-based discovery and annotation of protein-coding genes in eukaryotic metagenomic contigs. It performs fast searches with 6-frame-translated fragments covering all possible exons and optimally combines matches into multi-exon proteins. We used a benchmark of seven diverse, annotated genomes to show that MetaEuk is highly sensitive even under conditions of low sequence similarity to the reference database. To demonstrate MetaEuk’s power to discover novel eukaryotic proteins in large-scale metagenomic data, we assembled contigs from 912 samples of the Tara Oceans project. MetaEuk predicted >12,000,000 protein-coding genes in eight days on ten 16-core servers. Most of the discovered proteins are highly diverged from known proteins and originate from very sparsely sampled eukaryotic supergroups.

Conclusion

The open-source (GPLv3) MetaEuk software (https://github.com/soedinglab/metaeuk) enables large-scale eukaryotic metagenomics through reference-based, sensitive taxonomic and functional annotation.
Emergent honeycomb topology of the leaf spongy mesophyll
Authors: Borsuk Aleca M. , Roddy Adam B. , Théroux-Rancourt Guillaume , Brodersen Craig R.
Published: November 2019

The spongy mesophyll layer in leaves is ubiquitous among vascular plants, yet its structure is relatively unknown and typically described as a disordered assemblage of isodiametric cells. We characterized spongy mesophyll structure among diverse taxa using X-ray microCT imaging and found that leaves with small cell sizes, high cell packing densities, and close vein spacing were congruent with the isodiametric paradigm. When these structural traits exceeded well-defined thresholds, the spongy mesophyll domain was instead tessellated with an emergent topological motif of an irregular honeycomb that minimizes cellular investment and obeys Euler’s Law of space filling. Our data suggest spongy mesophyll is governed by allometric scaling laws, with two distinct topologies optimized for either photosynthetic performance or minimal resource investment.

One Sentence Summary

Conserved topological motifs in the spongy mesophyll are coordinated with leaf photosynthetic performance.
Ectomycorrhizal fungi induce systemic resistance against insects on a non-mycorrhizal plant in a CERK1-dependent manner
Authors: Vishwanathan Kishore , Zienkiewicz Krzysztof , Liu Yang , Janz Dennis , Feussner Ivo , Polle Andrea , Haney Cara H.
Published: November 2019

Below-ground microbes can induce systemic resistance (ISR) against foliar pests and pathogens on diverse plant hosts. The prevalence of ISR among plant-microbe-pest systems raises the question of host specificity in microbial induction of ISR. To test whether ISR is limited by plant host range, we tested the ISR-inducing ectomycorrhizal (ECM) fungus Laccaria bicolor on the non-mycorrhizal plant Arabidopsis. We found that root inoculation with L. bicolor triggered ISR against the insect herbivore Trichoplusia ni and induced systemic susceptibility (ISS) against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000 (Pto). We found that L. bicolor-triggered ISR against T. ni was dependent on jasmonic acid (JA) signaling and salicylic acid (SA) biosynthesis and signaling. We found that heat killed L. bicolor and chitin are sufficient to trigger ISR against T. ni and ISS against Pto and that the chitin receptor CERK1 is necessary for L. bicolor-mediated effects on systemic immunity. Collectively our findings suggest that some ISR responses might not require intimate co-evolution of host and microbe, but rather might be the result of root perception of conserved microbial signals.
Divergent strategies for learning in males and females
Authors: Chen Cathy S. , Ebitz R. Becket , Bindas Sylvia R. , Redish A. David , Hayden Benjamin Y. , Grissom Nicola M.
Published: November 2019

A frequent assumption in value-based decision-making tasks is that agents make decisions based on the feature dimension that reward probabilities vary on. However, in complex, multidimensional environments, stimuli can vary on multiple dimensions at once, meaning that the feature deserving the most credit for outcomes is not always obvious. As a result, individuals may vary in the strategies used to sample stimuli across dimensions, and these strategies may have an unrecognized influence on decision-making. Sex is a proxy for multiple genetic and endocrine influences that can influence decision-making strategies, including how environments are sampled. In this study, we examined the strategies adopted by female and male mice as they learned the value of stimuli that varied in both image and location in a visually-cued two-armed bandit, allowing two possible dimensions to learn about. Female mice acquired the correct image-value associations more quickly than male mice, and they used a fundamentally different strategy to do so. Female mice constrained their decision-space early in learning by preferentially sampling one location over which images varied. Conversely, male strategies were inconsistent, changing frequently and strongly influenced by the immediate experience of stochastic rewards. Individual strategies were related to sex-gated changes in neuronal activation in early learning. Together, we find that in mice, sex is linked with divergent strategies for sampling and learning about the world, revealing substantial unrecognized variability in the approaches implemented during value-based decision-making.
Enabling FIB-SEM Systems for Large Volume Connectomics and Cell Biology
Authors: Xu C. Shan , Pang Song , Hayworth Kenneth J. , Hess Harald F.
Published: November 2019

Isotropic high-resolution imaging of large volumes provides unprecedented opportunities to advance connectomics and cell biology research. Conventional Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) offers unique benefits such as high resolution (< 10 nm in x, y, and z), robust image alignment, and minimal artifacts for superior tracing of neurites. However, its prevailing deficiencies in imaging speed and duration cap the maximum possible image volume. We have developed technologies to overcome these limitations, thereby expanding the image volume of FIB-SEM by more than four orders of magnitude from 103µm3to 3 x 107µm3while maintaining an isotropic resolution of 8 x 8 x 8 nm3voxels. These expanded volumes are now large enough to support connectomic studies, in which the superior z resolution enables automated tracing of fine neurites and reduces the time-consuming human proofreading effort. Moreover, by trading off imaging speed, the system can readily be operated at even higher resolutions achieving voxel sizes of 4 x 4 x 4 nm3, thereby generating ground truth of the smallest organelles for machine learning in connectomics and providing important insights into cell biology. Primarily limited by time, the maximum volume can be greatly extended.

Here we provide a detailed description of the enhanced FIB-SEM technology, which has transformed the conventional FIB-SEM from a laboratory tool that is unreliable for more than a few days to a robust imaging platform with long term reliability: capable of years of continuous imaging without defects in the final image stack. An in-depth description of the systematic approach to optimize operating parameters based on resolution requirements and electron dose boundary conditions is also explicitly disclosed. We further explore how this technology unleashes the full potential of FIB-SEM systems, revolutionizing volume electron microscopy (EM) imaging for biology by gaining access to large sample volumes with single-digit nanoscale isotropic resolution.
Insilico Analysis Reveal Three novel nsSNPs May effect onGM2Aprotein Leading to AB variant of GM2 gangliosidosis
Authors: Abdelhameed Tebyan A. , Mustafa Mujahed I. , Abdelrahman Dina N. , Abdelrhman Fatima A. , Hassan Mohamed A.
Published: November 2019

Background

AB variant of GM2 gangliosidosis caused as a result of mutations in GM2 activator gene (GM2A) which is regarded as neurodegenerative disorder. This study aimed to predict the possible damaging SNPs of this gene and their impact on the protein using different bioinformatics tools.

Methods

SNPs retrieved from the NCBI database were analyzed using several bioinformatics tools. The different tools collectively predicted the effect of single nucleotide substitution on both structure and function of GM2 activator.

Results

Three novel mutations were found to be highly damaging to the structure and function of theGM2Agene.

Conclusion

Four SNPs were found to be highly damaging SNPs that affect function, structure and stability ofGM2Aprotein, which they are: C99Y, C112F, C138S and C138R, three of them are novel SNPs (C99Y, C112F and C138S). Also 46 SNPs were predicted to affect miRNAs binding sites on 3’UTR leading to abnormal expression of the resulting protein. These SNPs should be considered as important candidates in causing AB variant of GM2 gangliosidosis and may help in diagnosis and genetic screening of the disease.
Reference-free deconvolution of complex DNA methylation data – a systematic protocol
Authors: Scherer Michael , Nazarov Petr V. , Toth Reka , Sahay Shashwat , Kaoma Tony , Maurer Valentin , Plass Christoph , Lengauer Thomas , Walter Jörn , Lutsik Pavlo
Published: November 2019

Epigenomic profiling enables unique insights into human development and diseases. Often the analysis of bulk samples remains the only feasible option for studying complex tissues and organs in large patient cohorts, masking the signatures of important cell populations in convoluted signals. DNA methylomes are highly cell type-specific, and enable recovery of hidden components using advanced computational methods without the need for reference profiles. We propose a three-stage protocol for reference-free deconvolution of DNA methylomes comprising: (i) data preprocessing, confounder adjustment and feature selection, (ii) deconvolution with multiple parameters, and (iii) guided biological inference and validation of deconvolution results. Our protocol simplifies the analysis and integration of DNA methylomes derived from complex samples, including tumors. Applying this protocol to lung cancer methylomes from TCGA revealed components linked to stromal cells, tumor-infiltrating immune cells, and associations with clinical parameters. The protocol takes less than four days to complete and requires basic R skills.