bluuebunny/crossref_metadata_2025 huggingface dataset:
Computation and application of tissue-specific gene set weights
Authors: Frost H Robert
Published: April 2018

Motivation

Gene set testing, or pathway analysis, has become a critical tool for the analysis of high-dimensional genomic data. Although the function and activity of many genes and higher-level processes is tissue-specific, gene set testing is typically performed in a tissue agnostic fashion, which impacts statistical power and the interpretation and replication of results.

Results

To address this challenge, we have developed a bioinformatics approach to compute tissue-specific weights for individual gene sets using information on tissue-specific gene activity from the Human Protein Atlas (HPA). We used this approach to create a public repository of tissue-specific gene set weights for 37 different human tissue types from the HPA and all collections in the Molecular Signatures Database. To demonstrate the validity and utility of these weights, we explored three different applications: the functional characterization of human tissues, multi-tissue analysis for systemic diseases and tissue-specific gene set testing.

Availability and implementation

All data used in the reported analyses is publicly available. An R implementation of the method and tissue-specific weights for MSigDB gene set collections can be downloaded at http://www.dartmouth.edu/∼hrfrost/TissueSpecificGeneSets.
The Influence of Purchase Motivation on Perceived Preference Uniqueness and Assortment Size Choice
Authors: Whitley Sarah C , Trudel Remi , Kurt Didem
Published: April 2018

The present research examines how hedonic and utilitarian purchase motivations influence consumers’ perceptions of their product preferences and the resulting number of options they wish to consider when making a purchase. Across six studies, consumers choose to review larger assortments when their purchase motivation is hedonic rather than when their purchase motivation is utilitarian. This effect occurs because consumers with hedonic purchase motivations perceive their product preferences as highly unique compared to consumers with utilitarian purchase motivations. Higher perceived preference uniqueness increases the difficulty consumers anticipate in finding a preference-matching product, resulting in an expansion of the number of product alternatives to review. Further supporting the perceived preference uniqueness account, the documented effect is attenuated when product assortments are customized based on consumers’ personal preferences and when a social similarity priming task is employed. These findings provide additional evidence on the distinction between hedonic and utilitarian purchase motivations, their impact on perceived preference uniqueness, and their implications for consumer decision making via assortment size choice.
First United States Outbreak of Mycobacterium abscessus Hand and Foot Disease Among Children Associated With a Wading Pool
Authors: Carter Kris K , Lundgren Ingrid , Correll Sarah , Schmalz Tom , McCarter Tammie , Stroud Joshua , Bruesch Amanda , Hahn Christine G
Published: April 2018

Background

Mycobacterium abscessus, an emerging pathogen in healthcare settings, has rarely been associated with community outbreaks. During February–May 2013, Idaho public health officials and pediatric infectious disease physicians investigated an outbreak of M abscessus skin infections in children whose only common exposure was an indoor wading pool.

Methods

Healthcare providers and parents reported possible M abscessus cases. We used a standardized questionnaire to interview parents of affected children. Clinical specimens were submitted for mycobacterial examination. We conducted an environmental investigation of the pool. Microbial isolates from clinical and environmental samples were identified by sequencing polymerase chain reaction amplicons and underwent pulsed-field gel electrophoresis.

Results

Twelve cases were identified. Specimens from 4 of 7 children grew M abscessus or Mycobacterium abscessus/Mycobacterium chelonae . Ten (83%) of 12 children were female; median age was 3 years (range, 2 to 6 years); and all were immunocompetent. Pool maintenance did not fully comply with Idaho state rules governing pool operation. Mycobacterium abscessus/chelonae was isolated from pool equipment. Pulsed-field gel electrophoresis composite patterns were 87% similar between isolates from the pool ladder and 1 patient, and they were 90% similar between isolates from 2 patients. Environmental remediation included hyperchlorination, scrubbing and disinfection of pool surfaces, draining the pool, and replacement of worn pool materials.

Conclusions

Immunocompetent children acquired M abscessus cutaneous infection involving hands and feet after exposure to a wading pool. Environmental remediation and proper pool maintenance likely halted transmission. Medical and public health professionals’ collaboration effectively detected and controlled an outbreak caused by an emerging recreational waterborne pathogen.
Videoconferenced Telebehavioral Health Referral Process Adherence
Authors: Tebbs Jeffrey
Published: April 2018

Background

In 2015, the Army mandated 100% digital storage of telehealth consent forms (DA4700) in the Health Artifact and Image Management Solution (HAIMS) system, and a telebehavioral health (TBH) hub clinic set an aim to accomplish this by improving adherence to referral procedures essential to expanding patient access to videoconferenced (VC) behavioral health care.

Methods

The Knowledge-to-Action (KTA) planned action framework underpinned development of a two-phase, PDSA (Plan-Do-Study-Act) quality improvement project to increase the rates of TBH new intake consent form completeness and upload adherence. First, a provider education initiative addressed form uploads. Second, TBH consultants prepared (signed and sent) intake forms to referring sites for their patients to finalize during the initial VC encounter. A chart review of consecutive new intake encounters compared data extracted from CY2015 Q1 baseline records (n = 65) with data from CY2016 Q1 improvement period records (n = 40). A total of 352 forms were reviewed.

Results

Referrals (N = 118) that resulted in kept new VC TBH intake visits (n = 105), originated from three military behavioral health clinic referral sites. In CY2016 Q1, all DA4700 consent forms were uploaded to HAIMS. Telehealth treatment and medication consent form upload adherence increased from 94% and 68%, respectively, to 100% (p > 0.05). Form completeness increased from 36% to 95% (p < 0.001), and multiple linear regression analysis predicted an average 59% increase across the three referral sites (sr2 = 0.54).

Conclusion

Consultant preparation of telehealth new intake consent forms effectively improved form completeness and increased adherence to new intake referral processes essential to this hub clinic expanding patient access to TBH care.
Medical Device Connectivity Challenges Outline the Technical Requirements and Standards For Promoting Big Data Research and Personalized Medicine in Neurocritical Care
Authors: Rodriguez Anna , Smielewski Peter , Rosenthal Eric , Moberg Dick
Published: April 2018

Brain injuries are complicated medical problems and their management requires data from disparate sources to extract actionable information. In neurocritical care, interoperability is lacking despite the perceived benefits. Several efforts have been underway, but none have been widely adopted, underscoring the difficulty of achieving this goal. We have identified the current pain points of data collection and integration based on the experience with two large multi-site clinical studies: Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) in the United States and Collaborative European Neuro Trauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) in Europe. The variability of measurements across sites remains a barrier to uniform data collection. We found a need for annotation standards and for a standardized archive format for high-resolution data. Overall, the hidden cost for successful data collection was initially underestimated.

Although the use of bedside data integration solutions, such as the Moberg’s Component Neuromonitoring System (Moberg Research, Inc., Ambler, PA, USA) or ICM+ software (Cambridge Enterprise, Cambridge, UK), facilitated the homogenous collection of synchronized data, there remain issues that need to be addressed by the neurocritical care community. To this end, we have organized a Working Group on Neurocritical Care Informatics, whose next step is to create an overarching informatics framework that takes advantage of the collected information to answer scientific questions and to accelerate the translation of trial results to actions benefitting military medicine.
ASASSN-16dt and ASASSN-16hg: Promising candidate period bouncers
Authors: Kimura Mariko , Isogai Keisuke , Kato Taichi , Taguchi Kenta , Wakamatsu Yasuyuki , Hambsch Franz-Josef , Monard Berto , Myers Gordon , Dvorak Shawn , Starr Peter , Brincat Stephen M , de Miguel Enrique , Ulowetz Joseph , Itoh Hiroshi , Stone Geoff , Nogami Daisaku
Published: April 2018

We present optical photometry of superoutbursts that occurred in 2016 of two WZ Sge-type dwarf novae (DNe), ASASSN-16dt and ASASSN-16hg. Their light curves showed a dip in brightness between the first plateau stage with no ordinary superhumps (or early superhumps) and the second plateau stage with ordinary superhumps. We find that the dip is produced by the slow evolution of the 3 : 1 resonance tidal instability and that it would likely be observed in low mass-ratio objects. An estimated mass ratio (q ≡ M2/M1) from the period of developing (stage A) superhumps [0.06420(3) d] was 0.036(2) in ASASSN-16dt. Additionally, its superoutburst has many properties similar to those in other low-q WZ Sge-type DNe: long-lasting stage-A superhumps, small superhump amplitudes, long delay of ordinary-superhump appearances, and a slow decline rate in the plateau stage with superhumps. Its very small mass ratio and observational characteristics suggest that this system is one of the best candidates for a period bouncer—a binary accounting for the missing population of post-period minimum cataclysmic variables. Although it is not clearly verified due to the lack of detection of stage-A superhumps, ASASSN-16hg might be a possible candidate for period bouncers on the basis of the morphology of its light curves and the small superhump amplitudes. Many outburst properties of period bouncer candidates would originate from the small tidal effects of their secondary stars.
Does losing a parent early influence the education you obtain? A nationwide cohort study in Denmark
Authors: Høeg B L , Johansen C , Christensen J , Frederiksen K , Dalton S Oksbjerg , Bøge P , Dencker A , Dyregrov A , Bidstrup P E
Published: April 2018

Background

Health inequalities are rooted in education and we investigate the association between early parental death and attainment across the educational spectrum.

Methods

Using total population data on Danes born between 1982 and 2000 (n = 1 043 813), we assess incidence rate ratios (RRs) by gender for attainment of each educational level (basic school, high school or vocational training, bachelor degree or professional programme, and university graduate degree) according to loss of a parent before the age of 18 years. We adjust for family income, education and psychiatric illness and examine parent’s gender, cause of death and child’s age at time of death as potential moderators.

Results

Bereaved people had significantly lower attainment rates than non-bereaved people: basic school (RR = 0.95; 95% CI: 0.93–0.97 for men and 0.96; 0.94–0.98 for women), high school or vocational training (0.78; 0.76–0.80 for men and 0.82; 0.80–0.84 for women), bachelor degree or professional programme (0.74; 0.70–0.79 for men and 0.83; 0.79–0.86 for women) and university graduate degree (0.77; 0.68–0.86 for men and 0.77; 0.69–0.86 for women). Parent’s gender, cause of death and child’s age at the death did not modify the associations.

Conclusions

As education impacts population health, support for bereaved school children may be more important than realized.
From pure science to participatory knowledge production? Researchers’ perceptions on science–policy interface in bioenergy policy
Authors: Saarela Sanna-Riikka
Published: April 2018

There is a plea for dialogue and interaction between researchers and policymakers, particularly in relation to burning and complex societal problems. However, day-to-day science–policy interaction remains a challenge. By investigating researchers’ perspectives on challenges and opportunities of evolving interaction between science and policy, this article contributes to the ongoing discussions on workable and effective science–policy interface. The analysis, based on twelve in-depth interviews with experienced forest bioenergy researchers working at different organizations in Finland, shows that researchers appreciate a variety of roles and contributions from pure scientist to participatory knowledge production. Paradoxically, researchers ideologically still adhere to objective and linear knowledge production, which is, however, associated with multiple challenges such as politicization of science, disuse or misuse of scientific knowledge and communication. The article concludes that more nuanced consideration and acknowledgement of science–policy context as well as researchers’ role in it could create mutual benefits for research and policy.
Extreme work hours in Western Europe and North America: diverging trends since the 1970s
Authors: Burger Anna S
Published: April 2018

This article presents a political economy analysis of extreme work hours in 18 advanced Western economies since the 1970s. Empirically, it shows that the culture of long work hours has gained significance not only in the Anglo-Saxon but also in most Continental European welfare states. Theoretically, it provides an institutionalist argument against the neoclassical, or supply-side, point of view on the drivers of long work hours in post-industrial labour markets. It demonstrates that the choice to work long hours is not entirely, or even mainly, left to the preference of the individual. Instead, individual choices are constrained by labour market policies, collective bargaining institutions and new labour market structures, the pattern and trends of which do not necessarily follow the contours of the regime typology. Data on extreme work hours was compiled from the Luxembourg Income Study and the Multinational Time Use Study micro-data collections.
National Internal Medicine Milestone Ratings: Validity Evidence From Longitudinal Three-Year Follow-up
Authors: Hauer Karen E. , Vandergrift Jonathan , Lipner Rebecca S. , Holmboe Eric S. , Hood Sarah , McDonald Furman S.
Published: April 2018

Purpose

To evaluate validity evidence for internal medicine milestone ratings across programs for three resident cohorts by quantifying “not assessable” ratings; reporting mean longitudinal milestone ratings for individual residents; and correlating medical knowledge ratings across training years with certification examination scores to determine predictive validity of milestone ratings for certification outcomes.

Method

This retrospective study examined milestone ratings for postgraduate year (PGY) 1–3 residents in U.S. internal medicine residency programs. Data sources included milestone ratings, program characteristics, and certification examination scores.

Results

Among 35,217 participants, there was a decreased percentage with “not assessable” ratings across years: 1,566 (22.5%) PGY1s in 2013–2014 versus 1,219 (16.6%) in 2015–2016 (P= .01), and 342 (5.1%) PGY3s in 2013–2014 versus 177 (2.6%) in 2015–2016 (P= .04). For individual residents with three years of ratings, mean milestone ratings increased from around 3 (behaviors of an early learner or advancing resident) in PGY1 (ranging from a mean of 2.73 to 3.19 across subcompetencies) to around 4 (ready for unsupervised practice) in PGY3 (mean of 4.00 to 4.22 across subcompetencies,P< .001 for all subcompetencies). For each increase of 0.5 units in two medical knowledge (MK1, MK2) subcompetency ratings, the difference in examination scores for PGY3s was 19.5 points for MK1 (P< .001) and 19.0 for MK2 (P< .001).

Conclusions

These findings provide evidence of validity of the milestones by showing how training programs have applied them over time and how milestones predict other training outcomes.
Educational Interventions to Improve Handover in Health Care: An Updated Systematic Review
Authors: Gordon Morris , Hill Elaine , Stojan Jennifer N. , Daniel Michelle
Published: April 2018

Purpose

Effective handovers (handoffs) are vital to patient safety. Medical educators investigated educational interventions to improve handovers in a 2011 systematic review. The number of publications on handover education has increased since then, so authors undertook this updated review.

Method

The authors considered studies involving educational interventions to improve handover amongst undergraduate or postgraduate health professionals in acute care settings. In September 2016, two authors independently conducted a standardized search of online databases and completed a data extraction and quality assessment of the articles included. They conducted a content analysis of and extracted key themes from the interventions described.

Results

Eighteen reports met the inclusion criteria. All but two were based in the United States. Interventions most commonly involved single-patient exercises based on simulation and role-play. Many studies mentioned multiprofessional education or practice, but interventions occurred largely in single-professional contexts. Analysis of interventions revealed three major themes: facilitating information management, reducing the potential for errors, and improving confidence. The majority of studies assessed Kirkpatrick’s outcomes of satisfaction and knowledge/skill improvement (Levels 1 and 2). The strength of conclusions was generally weak.

Conclusions

Despite increased interest in and publications on handover, the quality of published research remains poor. Inadequate reporting of interventions, especially as they relate to educational theory, pedagogy, curricula, and resource requirements, continues to impede replication. Weaknesses in methodologies, length of follow-up, and scope of outcomes evaluation (Kirkpatrick levels) persist. Future work to address these issues, and to consider the role of multiprofessional and multiple-patient handovers, is vital.
Immunogenicity and Reactogenicity of DTPa-HBV-IPV/Hib and PHiD-CV When Coadministered With MenACWY-TT in Infants
Authors: Merino Arribas Jose Manuel , Carmona Martínez Alfonso , Horn Michael , Perez Porcuna Xavier Maria , Otero Reigada Maria del Carmen , Marès Bermúdez Josep , Centeno Malfaz Fernando , Miranda Mariano , Mendez Maria , Garcia Cabezas Miguel Angel , Christoph Wittermann , Bleckmann Gerhard , Fischbach Thomas , Kolhe Devayani , Van der Wielen Marie , Baine Yaela
Published: April 2018

Background:

This study evaluated the immunogenicity and reactogenicity of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus virus-Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) and a 10-valent pneumococcal conjugate vaccine (PHiD-CV) coadministered with a quadrivalent meningococcal conjugate vaccine (MenACWY-TT) in infants/toddlers.

Methods:

In this open, controlled, phase III study (NCT01144663), 2095 healthy infants were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age or MenACWY-TT, MenC-CRM197, or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa-HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immunogenicity of DTPa-HBV-IPV/Hib was evaluated in exclusive randomized subsets of 25% of participants from each group postprimary, prebooster and postbooster vaccination, whereas immunogenicity of PHiD-CV was evaluated at all time points. Reactogenicity was evaluated on the total vaccinated cohorts during 8 days after each vaccination.

Results:

For each DTPa-HBV-IPV/Hib antigen, ≥97.2%, ≥76.5% and ≥97.9% of participants had seropositive/seroprotective levels 1 month postprimary vaccination, before the booster dose and 1 month postbooster, respectively. For each vaccine pneumococcal serotype, ≥74.0% of infants had antibody concentrations ≥0.35 μg/mL at 1 month postprimary vaccination, and robust increases in antibody geometric mean concentrations were observed from prebooster to postbooster. Redness was the most frequent solicited local symptom at the DTPa-HBV-IPV/Hib and PHiD-CV injection sites, reported after up to 47.7% and 57.0% of doses postprimary and postbooster vaccination, respectively.

Conclusions:

Primary and booster vaccinations of infants/toddlers with DTPa-HBV-IPV/Hib and PHiD-CV coadministered with MenACWY-TT were immunogenic with clinically acceptable reactogenicity profiles. These results support the coadministration of MenACWY-TT with routine childhood vaccines.
Back to Basics: Adherence With Guidelines for Glucose and Temperature Control in an American Comprehensive Stroke Center Sample
Authors: Alexandrov Anne W. , Palazzo Paola , Biby Sharon , Doerr Abbigayle , Dusenbury Wendy , Young Rhonda , Lindstrom Anne , Grove Mary , Tsivgoulis Georgios , Middleton Sandy , Alexandrov Andrei V.
Published: April 2018

Background: Variance from guideline-directed care for glucose and temperature control remains unknown in the United States at a time when priorities have shifted to ensure rapid diagnosis and treatment of acute stroke patients. However, protocol-driven nursing surveillance for control of hyperglycemia and hyperthermia has been shown to improve patient outcomes. Methods: We conducted an observational pilot study to assess compliance with American guidelines for glucose and temperature control and association with discharge outcomes in consecutive acute stroke patients admitted to 5 US comprehensive stroke centers. Data for the first 5 days of stroke admission were collected from electronic medical records and entered and analyzed in SPSS using descriptive statistics, Mann-Whitney U test, Student t tests, and logistic regression. Results: A total of 1669 consecutive glucose and 3782 consecutive temperature measurements were taken from a sample of 235 acute stroke patients; the sample was 87% ischemic and 13% intracerebral hemorrhage. Poor glucose control was found in 33% of patients, and the most frequent control method ordered (35%) was regular insulin sliding scale without basal dosing. Poor temperature control was noted in 10%, and 39% did not have temperature recorded in the emergency department. Lower admission National Institutes of Health Stroke Scale score and well-controlled glucose were independent predictors of favorable outcome (discharge modified Rankin Scale score, 0–2) in reperfusion patients. Conclusion: Glucose and temperature control may be overlooked in this era of rapid stroke diagnosis and treatment. Acute stroke nurses are well positioned to assume leadership of glucose and temperature monitoring and treatment.
Methods of Identifying Limb Dominance in Adolescent Female Basketball Players: Implications for Clinical and Biomechanical Research
Authors: Mulrey Colleen R. , Shultz Sandra J. , Ford Kevin R. , Nguyen Anh-Dung , Taylor Jeffrey B.
Published: April 2018

Objective:

To identify relationships between self-reported limb preferences and performance measures for determining limb dominance in adolescent female basketball players.

Design:

Cross-sectional cohort study.

Participants:

Forty adolescent female basketball players.

Independent Variables and Main Outcome Measures:

Participants provided self-reported preferred kicking and jumping limbs, then completed 3 trials of a single-limb countermovement hop (HOPVER) and unilateral triple hop for distance (HOPHOR) on each limb. Each test was used to independently define limb dominance by the limb that produced the largest maximum vertical height and horizontal distance, respectively.

Results:

Chi-square tests for independence identified a significant relationship between self-reported preferred kicking and jumping legs (χ2 = 7.41, P = 0.006). However, no significant relationships were found when comparing self-reported preference to measures of performance during the HOPHOR (χ2 = 0.33, P = 0.57) or HOPVER (χ2 = 0.06, P = 0.80). In addition, the 2 performance measures did not consistently produce the same definition of limb dominance among individuals (χ2 = 1.52, P = 0.22).

Conclusions:

Self-selection of the dominant limb is unrelated to performance. Furthermore, limb dominance, as defined by vertical jump height, is unrelated to limb dominance defined by horizontal jump distance. The results of this study call into question the validity of consistently defining limb dominance by self-reported measures in adolescent female basketball players.
Muscle Strength, Power, and Torque Deficits in Children With Type SS Sickle Cell Disease
Authors: Dougherty Kelly A. , Bertolaso Chiara , Schall Joan I. , Smith-Whitley Kim , Stallings Virginia A.
Published: April 2018

In African-American children aged 5 to 17 years with and without type SS sickle cell disease (SCD-SS), dominant hand maximal handgrip strength, peak power, and plantar flexion isometric maximal voluntary contraction (MVC) torque were compared with adjustments for body size and composition. Children with SCD-SS (n=21; age, 11±1 y) compared with healthy control children (n=23; 10±1 y) did not differ by age, sex, or maturation stage, but had significantly lower Z scores for height, weight, body mass index, arm circumference, upper arm muscle area, and lean mass-for-height. Children with SCD-SS had significantly lower unadjusted handgrip strength (16±2 vs. 23±2 kg, P<0.01), peak power (1054±107 vs. 1488±169 W, P<0.04) and MVC torques at 2 angles (10 degrees: 27±3 vs. 42±5 Nm; 20 degrees: 21±3 vs. 34±4 Nm; all P<0.05). Performance decrements persisted when handgrip strength was adjusted for lean body mass and fat mass explaining 66% of the variance; peak power adjusted for age, lean body mass, fat mass, and height explaining 91% of the variance; and the highest MVC torque (10-degree angle) adjusted for left leg length, lean mass-for-height, and fat mass-for-height Z scores explaining 65% of the variance. This suggests additional factors contribute to the attenuated anaerobic performance.
The effects of tongue pressure strength and accuracy training on tongue pressure strength, swallowing function, and quality of life in subacute stroke patients with dysphagia: a preliminary randomized clinical trial
Authors: Moon Jong-Hoon , Hahm Suk-Chan , Won Young Sik , Cho Hwi-Young
Published: April 2018

Tongue pressure strength and accuracy training (TPSAT) has been proposed as an intervention to improve dysphagia. However, the effects of TPSAT on dysphagia in subacute stroke patients remain unclear. The aim of this study was to investigate the effects of TPSAT on tongue pressure strength, swallowing function, and quality of life in subacute stroke patients with dysphagia. Sixteen subacute stroke patients were assigned randomly to two groups: the TPSAT group (n=8) or the control group (n=8). In the former, both TPSAT and traditional dysphagia therapies were performed for 30 min each per day; in the latter, only traditional dysphagia therapy was performed for 30 min twice a day. Both groups performed each daily intervention five times per week for 8 weeks. To assess the tongue pressure strength, maximum isometric tongue pressures (MIPs) of the anterior and posterior tongue using the Iowa Oral Performance Instrument were measured before and after the intervention. Mann Assessment of Swallowing Ability (MASA) and Swallowing-Quality of Life (SWAL-QOL) were also used to assess the swallowing function and quality of life, respectively. TPSAT with traditional dysphagia therapy significantly improved MASA, SWAL-QOL, and MIPs both anteriorly and posteriorly, and traditional dysphagia therapy significantly increased MASA, SWAL-QOL, and MIPs anteriorly (P<0.05). The TPSAT group showed a significant improvement in anterior and posterior MIPs and tongue movement score in MASA compared with the control group (P<0.05). Our findings suggest that TPSAT may significantly improve dysphagia management in subacute stroke patients.
Mucolipidosis Type II Affecting 1 Fetus and Placental Disk of a Dichorionic-Diamnionic Twin Gestation: A Case Report and Review of the Literature
Authors: Chapel David B. , Choy Bonnie , Pytel Peter , Husain Aliya N. , Lastra Ricardo R.
Published: April 2018

Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality. On microscopic examination, the affected placenta displayed marked vacuolization of the syncytiotrophoblast and Hofbauer cells, which was confirmed on ultrastructural examination. To our knowledge, this is the first description of placental findings in a twin pregnancy, wherein only 1 twin is affected by an inborn error of metabolism. This provides an opportunity to highlight the placental abnormalities seen in this group of diseases, and to emphasize the role of pathologic examination in early detection of otherwise unsuspected inborn errors of metabolism.
Genetic diversity and drivers of dwarfism in extinct island emu populations
Authors: Thomson Vicki A. , Mitchell Kieren J. , Eberhard Rolan , Dortch Joe , Austin Jeremy J. , Cooper Alan
Published: April 2018

Australia's iconic emu (Dromaius novaehollandiae novaehollandiae) is the only living representative of its genus, but fossil evidence and reports from early European explorers suggest that three island forms (at least two of which were dwarfs) became extinct during the nineteenth century. While one of these—the King Island emu—has been found to be conspecific with Australian mainland emus, little is known about how the other two forms—Kangaroo Island and Tasmanian emus—relate to the others, or even the size of Tasmanian emus. We present a comprehensive genetic and morphological analysis ofDromaiusdiversity, including data from one of the few definitively genuine Tasmanian emu specimens known. Our genetic analyses suggest that all the island populations represent sub-populations of mainlandD.novaehollandiae. Further, the size of island emus and those on the mainland appears to scale linearly with island size but not time since isolation, suggesting that island size—and presumably concomitant limitations on resource availability—may be a more important driver of dwarfism in island emus, though its precise contribution to emu dwarfism remains to be confirmed.
De novo synthetic biliprotein design, assembly and excitation energy transfer
Authors: Mancini Joshua A. , Sheehan Molly , Kodali Goutham , Chow Brian Y. , Bryant Donald A. , Dutton P. Leslie , Moser Christopher C.
Published: April 2018

Bilins are linear tetrapyrrole chromophores with a wide range of visible and near-visible light absorption and emission properties. These properties are tuned upon binding to natural proteins and exploited in photosynthetic light-harvesting and non-photosynthetic light-sensitive signalling. These pigmented proteins are now being manipulated to develop fluorescent experimental tools. To engineer the optical properties of bound bilins for specific applications more flexibly, we have used first principles of protein folding to design novel, stable and highly adaptable bilin-binding four-α-helix bundle protein frames, called maquettes, and explored the minimal requirements underlying covalent bilin ligation and conformational restriction responsible for the strong and variable absorption, fluorescence and excitation energy transfer of these proteins. Biliverdin, phycocyanobilin and phycoerythrobilin bind covalently to maquette Cysin vitro. A blue-shifted tripyrrole formed from maquette-bound phycocyanobilin displays a quantum yield of 26%. Although unrelated in fold and sequence to natural phycobiliproteins, bilin lyases nevertheless interact with maquettes during co-expression inEscherichia colito improve the efficiency of bilin binding and influence bilin structure. Bilins bindin vitroandin vivoto Cys residues placed in loops, towards the amino end or in the middle of helices but bind poorly at the carboxyl end of helices. Bilin-binding efficiency and fluorescence yield are improved by Arg and Asp residues adjacent to the ligating Cys on the same helix and by His residues on adjacent helices.
Particular popular science: British scientists writing, speaking and broadcasting on science and religion from the 1980
s
Authors: Merchant Paul
Published: April 2018

This paper draws on extended life story oral history interviews with scientists who, beginning in the 1980s, turned to writing popular books, making radio and television programmes and taking to the stage for public lectures and debates, with relations between science and religion often a key topic: Peter Atkins, Nicholas Humphrey, Steve Jones, John Polkinghorne, Russell Stannard and Lewis Wolpert. I show that these interviews capture aspects of motivation and experience missed in much existing work on popular science. Stressing historical and individual particularity, I argue that what these scientists say about their decisions, aims and rewards should make us question a strong tendency in recent scholarship both to regard popular science as part of scientific work in general, and also to read the outcomes of popular science – such as advocacy for science or the promotion of certain theories – as the motivations for its production.
Identification of potent chromone embedded [1,2,3]-triazoles as novel anti-tubercular agents
Authors: Nalla Viswanadh , Shaikh Aslam , Bapat Sanket , Vyas Renu , Karthikeyan M. , Yogeeswari P. , Sriram D. , Muthukrishnan M.
Published: April 2018

A series of 20 novel chromone embedded [1,2,3]-triazoles derivatives were synthesized via an easy and convenient synthetic procedure starting from 2-hydroxy acetophenone. The
in vitro
anti-mycobacterial evaluation studies carried out in this work reveal that seven compounds exhibit significant inhibition against
Mycobacterium tuberculosis
H37Rv strain with MIC in the range of 1.56–12.5 µg ml
−1
. Noticeably, compound
6s
was the most potent compound
in vitro
with a MIC value of 1.56 µg ml
−1
. Molecular docking and chemoinformatics studies revealed that compound
6s
displayed drug-like properties against the enoyl-acyl carrier protein reductase of
M. tuberculosis
further establishing its potential as a potent inhibitor.
Sexual phenotype drives variation in endocrine responses to social challenge in a quasi-clonal animal
Authors: Li Cheng-Yu , Huang Shu-Ping , Garcia Mark , Fuller Adam , Hsu Yuying , Earley Ryan L.
Published: April 2018

In many species, males tend to behave more aggressively than females and female aggression often occurs during particular life stages such as maternal defence of offspring. Though many studies have revealed differences in aggression between the sexes, few studies have compared the sexes in terms of their neuroendocrine responses to contest experience. We investigated sex differences in the endocrine response to social challenge using mangrove rivulus fish,Kryptolebias marmoratus. In this species, sex is determined environmentally, allowing us to produce males and hermaphrodites with identical genotypes. We hypothesized that males would show elevated androgen levels (testosterone and 11-ketotestosterone) following social challenge but that hermaphrodite responses might be constrained by having to maintain both testicular and ovarian tissue. To test this hypothesis, we staged fights between males and between hermaphrodites, and then compared contest behaviour and hormone responses between the sexes. Hermaphrodites had significantly higher oestradiol but lower 11-ketotestosterone than males before contests. Males took longer to initiate contests but tended to fight more aggressively and sustain longer fights than hermaphrodites. Males showed a dramatic post-fight increase in 11-ketotestosterone but hermaphrodites did not. Thus, despite being genetically identical, males and hermaphrodites exhibit dramatically different fighting strategies and endocrine responses to contests.
Circadian clock neurons mediate time-of-day dependent responses to light
Authors: Jones Jeff R. , Simon Tatiana , Lones Lorenzo , Herzog Erik D.
Published: April 2018

Circadian (~24 h) rhythms influence nearly all aspects of physiology, including sleep/wake, metabolism, and hormone release. The suprachiasmatic nucleus (SCN) synchronizes these daily rhythms to the external light cycle, but the mechanisms by which this occurs is unclear. The neuropeptide vasoactive intestinal peptide (VIP) is the predominant contributor to synchrony within the SCN and is important for circadian light responses, but the role of VIP neurons themselves is unclear. Thus, we tested the hypothesis that rhythmic SCN VIP neurons mediate circadian light responses. Using in vivo fiber photometry recording of SCN VIP neurons we found daily rhythms in spontaneous calcium events that peaked during the subjective day and in light-evoked calcium events that exhibited the greatest response around subjective dusk. These rhythms were correlated with spontaneous and NMDA-evoked VIP release from SCN VIP neurons in vitro. Finally, in vivo hyperpolarization of VIP neurons attenuated light-induced shifts of daily rhythms in locomotion. We conclude that SCN VIP neurons are circadian and depolarize to light to modulate entrainment of daily rhythms in the SCN and behavior.
The expression of class II major histocompatibility molecules on breast tumors delays T cell exhaustion, expands the T cell repertoire and slows tumor growth
Authors: McCaw Tyler R. , Li Mei , Starenki Dmytro , Cooper Sara J. , Meza-Perez Selene , Arend Rebecca C. , LoBuglio Albert F. , Buchsbaum Donald J. , Forero Andres , Randall Troy D.
Published: April 2018

The expression of major histocompatibility complex II (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we tested how MHCII expression affected anti-tumor immunity. We found that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4+ and CD8+ T cells. Additionally, MHCII-expressing tumors contained more TCR clonotypes expanded to a larger degree than control tumors. Functional CD8+ T cells in tumors depended on CD4+ T cells. However, both CD4+ and CD8+ T cells eventually became exhausted, even in MHCII-expressing tumors. PD1 blockade had no impact on tumor growth, potentially because tumor cells poorly expressed PD-L1. These results suggest tumor cell expression of MHCII facilitates the local activation of CD4+ T cells and indirectly helps the activation and expansion of CD8+ T cells, but by itself, cannot prevent T cell exhaustion.

Précis

The expression of MHCII on tumor cells augments CD4 and CD8 T cell responses, expands the TCR repertoire and delays exhaustion. Hence, strategies to induce MHCII expression may be a powerful adjuvant to immunotherapeutic regimens of solid tumors.
Emergence of mosaic plasmids harboring Tn1546-ermBelement inStaphylococcus aureusisolates
Authors: Wan Tsai-Wen , Lin Yu-Tzu , Hung Wei-Chun , Tsai Jui-Chang , Liu Yu-Jung , Hsueh Po-Ren , Teng Lee-Jene
Published: April 2018

Antimicrobial resistance inStaphylococcus aureusis a major problem and the acquisition of resistance genes may occur by horizontal gene transfer (HGT). The transposon, an important means of HGT, is recognized as a mobile genetic element that can integrate in plasmids, replicate and transfer to other strains. We have previously reported a novel structure of theEnterococcus faecium-originated Tn1546-ermBelement inS. aureus. The emergence of the Tn1546-like element is an emerging problem that requires continuous monitoring. In the present study, we expand the examination of Tn1546-ermBelement toermB-positive methicillin-susceptibleS. aureus(MSSA) (n = 116) andermB-positive methicillin-resistantS. aureus(MRSA) (n = 253) during a 16-year period, from 2000 to 2015. PCR mapping showed that 10 MSSA and 10 MRSA carried the Tn1546-ermBelement. The 10 MSSA belonged to three sequence types (ST), ST7 (n = 6), ST5 (n = 3), and ST59 (n = 1), and the 10 MRSA belonged to two STs, ST188 (n = 8) and ST965 (n = 2). Since only clonal complex 5 (including ST5, ST85, ST231, and ST371) MRSA, ST8 MRSA and ST5 MSSA have been previously reported to carry Tn1546plasmids, this is the first report describing the presence of the Tn1546-ermBelement in ST7/5/59 MSSA and ST188/965 MRSA. Plasmid sequencing revealed that the Tn1546-ermBelement was harbored by five different mosaic plasmids. In addition to resistance genes, some plasmids also harbored toxin genes.
The biosynthetic origin of psychoactive kavalactones in kava
Authors: Pluskal Tomáš , Torrens-Spence Michael P. , Fallon Timothy R. , De Abreu Andrea , Shi Cindy H. , Weng Jing-Ke
Published: April 2018

For millennia, humans have used plants for medicinal purposes. However, our limited understanding of plant biochemistry hinders the translation of such ancient wisdom into modern pharmaceuticals1. Kava (Piper methysticum) is a medicinal plant native to the Polynesian islands with anxiolytic and analgesic properties supported by over 3,000 years of traditional use as well as numerous recent clinical trials2–5. The main psychoactive principles of kava, kavalactones, are a unique class of polyketide natural products known to interact with central nervous system through mechanisms distinct from those of the prescription psychiatric drugs benzodiazepines and opioids6,7. Here we reportde novoelucidation of the biosynthetic pathway of kavalactones, consisting of seven specialized metabolic enzymes. Based on phylogenetic and crystallographic analyses, we highlight the emergence of two paralogous styrylpyrone synthases, both of which have neofunctionalized from an ancestral chalcone synthase to catalyze the formation of the kavalactone scaffold. Structurally diverse kavalactones are then biosynthesized by subsequent regio- and stereo-specific tailoring enzymes. We demonstrate the feasibility of engineering heterologous production of kavalactones and their derivatives in bacterial, yeast, and plant hosts, thus opening an avenue towards the development of new psychiatric therapeutics for anxiety disorders, which affect over 260 million people globally8.
A scalable estimator of SNP heritability for Biobank-scale data
Authors: Wu Yue , Sankararaman Sriram
Published: April 2018

Motivation

Heritability, the proportion of variation in a trait that can be explained by genetic variation, is an important parameter in efforts to understand the genetic architecture of complex phenotypes as well as in the design and interpretation of genome-wide association studies. Attempts to understand the heritability of complex phenotypes attributable to genome-wide SNP variation data has motivated the analysis of large datasets as well as the development of sophisticated tools to estimate heritability in these datasets.

Linear Mixed Models (LMMs) have emerged as a key tool for heritability estimation where the parameters of the LMMs, i.e., the variance components, are related to the heritability attributable to the SNPs analyzed. Likelihood-based inference in LMMs, however, poses serious computational burdens.

Results

We propose a scalable randomized algorithm for estimating variance components in LMMs. Our method is based on a MoM estimator that has a runtime complexityfor N individuals andMSNPs (whereBis a parameter that controls the number of random matrix-vector multiplications). Further, by leveraging the structure of the genotype matrix, we can reduce the time complexity to.

We demonstrate the scalability and accuracy of our method on simulated as well as on empirical data. On standard hardware, our method computes heritability on a dataset of 500, 000 individuals and 100, 000 SNPs in 38 minutes.

Availability

The RHE-reg software is made freely available to the research community at:https://github.com/sriramlab/RHE-reg

Contact

sriram@cs.ucla.edu
Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion
Authors: Chen Yuchen , Ma Ningxin , Pei Zifei , Wu Zheng , Do-Monte Fabricio H. , Huang Pengqian , Yellin Emma , Chen Miranda , Yin Jiuchao , Lee Grace , Minier-Toribio Angélica , Hu Yi , Bai Yuting , Lee Kathryn , Quirk Gregory J. , Chen Gong
Published: April 2018

Mammalian brains have largely lost internal neural regeneration capability except for a few discrete neurogenic niches. After brain injury, the cerebral cortex is especially difficult to repair due to its extremely low rate of adult neurogenesis. Previous studies have converted glial cells into neurons, but the total number of neurons generated is rather limited, casting doubt about its therapeutic potential. Here, we demonstrate that high-efficiency neuroregeneration can be achieved in adult mammalian brains by making use of an engineered AAV Cre-FLEX system to convert a large number of reactive astrocytes into functional neurons. Specifically, using a combination of GFAP::Cre and FLEX-NeuroD1 AAV system, we were able to regenerate enough new neurons from astrocytes to cover about 40% of the neurons lost from an ischemic injury (400 NeuN+ new neurons/mm2), compared to previously reported an average of <1% of cortical neurons (2-8 NeuN+ neurons/mm2) in an ischemic-injured adult mammalian cortex. Importantly, this in situ astrocyte-to-neuron conversion process also improved survival of injured pre-existing neurons, (additional 400 neurons/mm2), leading to a repaired motor cortex with layered cortical structures. Moreover, NeuroD1-converted neurons not only form functional neural circuits but also rescue motor and memory deficits after ischemic injury. Our results establish the proof-of-principle that a highly efficient in situ astrocyte-to-neuron conversion approach provides a novel treatment for neurological disorders that are in need of new neurons.