bluuebunny/crossref_metadata_2025 huggingface dataset:
Measurement of Retinal Vessels as a Biomarker of Cerebrovascular Aging in Older HIV-Positive Men Compared With Controls
Authors: Haddow Lewis , Laverick Rosanna , Leung Irene , Post Frank , Vera Jaime , Gilson Richard , Williams Ian , Boffito Marta , Sabin Caroline , Winston Alan , Peto Tunde ,   on behalf of the Pharmacokinetic and Clinical Observations in People over Fifty (POPPY) study group
Published: October 2017

Background:

To compare retinal vascular measurements, biomarkers of cerebral small vessel disease, in HIV-positive men aged 50 years and older with similarly aged HIV-negative men and younger HIV-positive men.

Methods:

We recruited white, nondiabetic men into a cross-sectional substudy of a larger cohort including 3 demographically matched groups. Optic disc–centered 45-degree color fundus photographs were used to calculate central retinal arterial and venous caliber and the arterial–venous ratio (AVR). We used univariate and multivariable linear regression to compare retinal vessel measurements in the 3 groups and to identify factors associated with AVR.

Results:

All HIV-positive men were virologically suppressed. In a multivariable model, study group was not associated with AVR [adjusted β 0.010 for HIV-positive men <50 (n = 39) compared with HIV-positive men aged ≥50 years (n = 120), 95% confidence interval [CI] −0.018 to 0.038, P = 0.47; adjusted β 0.00002 for HIV-negative men ≥50 years (n = 52), 95% CI −0.022 to 0.022, P = 0.99]. Factors associated with lower AVR were systolic blood pressure (adjusted β −0.009 per +10 mm Hg, 95% CI −0.015 to −0.003, P = 0.002), history of stroke or transient ischemic attack (adjusted β −0.070, 95% CI −0.12 to −0.015, P = 0.01), and recent recreational drug use (adjusted β −0.037, 95% CI −0.057 to −0.018, P = 0.0002).

Conclusions:

There were no differences in retinal vascular indices between HIV-positive men aged ≥50 years and HIV-negative men aged ≥50 years or HIV-positive men aged <50 years, suggesting that HIV is not associated with an increased burden of cerebral small vessel disease.
Proposal of a Budget-Friendly Camera Holder for Endoscopic Ear Surgery
Authors: Ozturan Orhan , Yenigun Alper , Aksoy Fadlullah , Ertas Burak
Published: October 2017

Endoscopic ear surgery (EES) is increasingly a preferred technique in otologic society. It offers excellent visualization of the anatomical structures directly and behind the corners with variable angled telescopes. It also provides reduced operative morbidity due to being able to perform surgical interventions with less invasive approaches. Operative preparation and setup time and cost of endoscopy system are less expensive compared with surgical microscopes. On the other hand, the main disadvantage of EES is that the surgery has to be performed with 1 single hand. It is certainly restrictive for an ear surgeon who has been operating with 2 hands under otologic microscopic views for years and certainly requires a learning period and perseverance. Holding the endoscope by a second surgeon is not executable because of insufficient surgical space.

Endoscope/camera holders have been developed for those who need the comfort and convenience afforded by double-handed microscopic ear surgery. An ideal endoscope holder should be easy-to-set up, easily controlled, providing a variety of angled views, allowing the surgeon to operate with 2 hands and, budget-friendly. In this article, a commercially available 11-inch magic arm camera holder is proposed by the authors to be used in EES due to its versatile, convenient, and budget-friendly features. It allows 2-handed EES through existing technology and is affordable for surgeons looking for a low-cost and practical solution.
Longitudinal Assessment of Developmental Outcomes in Infants Undergoing Late Craniosynostosis Repair
Authors: Fontana Stefani C. , Belinger Skylar , Daniels Debby , Tuttle Margaret , Camarata Paul J. , Andrews Brian T.
Published: October 2017

Evaluation of infants with craniosynostosis for surgical intervention, as opposed to conservative management, remains a challenge within the field of craniofacial surgery. Studies have consistently demonstrated that surgical repair of craniosynostosis is ideally performed between 3 and 12 months of age. As such, there is limited data regarding neurocognitive development in infants who initially present with uncorrected craniosynostosis after 12 months of age. Moreover, the impact of cranial vault surgery on neurocognitive development at all ages remains under investigation. A prospective, nonrandomized study was performed. All children with nonsyndromic craniosynostosis who presented for initial evaluation after 12 months of age were enrolled. The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) was utilized to assess pre- and postoperative cognitive development and comparisons were made to normative values. Developmental delay is defined as scoring < 85. Five infants, average age 26 months (13–43 months) at initial presentation, underwent cranial vault remodeling and developmental testing. Fused cranial sutures involved: metopic (n = 4), and right coronal (n = 1). Cognitive testing demonstrated that 4 of 5 infants (80%) were developmentally delayed at presentation (scores: 60, 70, 72, and 80), and 1 infant was within normal limits (score: 100). Postoperative testing was performed between 2 and 12 months postoperatively. Universal improvement was observed in infants who were delayed prior to surgery (80, 80, 75, and 90, respectively). The infant who was not delayed prior to surgery remained within normal limits after surgery. This study demonstrates an association between cranial vault surgery and cognitive improvement in infants presenting late with developmental delay.
Extragingival Pregnancy Pyogenic Granuloma on the Lip
Authors: Canivell-Zabaleta Maitena , Martin-Lozano Guiomar , Olmos-Juarez Erika , Fontillon-Alberdi Maria , Infante-Cossio Pedro
Published: October 2017

Pregnancy pyogenic granuloma is considered a benign common growth that usually develops on the gingiva in the second and third trimester of gestation, in response to local irritation, trauma or hormonal factors. Here, the authors report a case of a primigravida who presented an extragingival pyogenic granuloma with a rapid progression in the post-partum. The occurrence on the lower lip in the first few days after delivery was a relatively rarity in the present case which provoked a meaningful state of anxiety and cancerophobia to the female. Complete excision was curative and brought immediate relief of pain and discomfort. This clinical report highlights the possibility of pyogenic granuloma presenting like a rapid-growing mass on the lip and the importance of clinical differential diagnosis of such presentation in this atypical location.
Vasopressor Cumulative Dose Requirement and Risk of Early Death During Septic Shock: An Analysis From The EPISS Cohort
Authors: Dargent Auguste , Nguyen Maxime , Fournel Isabelle , Bourredjem Abderrahmane , Charles Pierre-Emmanuel , Quenot Jean-Pierre
Published: October 2017

Septic shock is the primary cause of death in intensive care units, with about 20% of patients dying in the first 3 days. To design future trials focused on early mortality, we require knowledge of early indicators that can detect patients at high risk of early death from refractory septic shock. The aim of this study was to assess whether the cumulative dose of vasopressors (CDV), calculated as the cumulative dose of epinephrine + norepinephrine, is a predictor of early death (within 72 h) attributable to refractory septic shock (EDASS). This substudy of the EPISS trial was based on 370 patients admitted to a French ICU for septic shock between 2009 and 2011. The area under the receiving operating characteristic curve was calculated for the CDV at 6, 12, 24, 36, and 48 h after vasopressor initiation, and a strategy to predict the risk of EDASS was built based on selected times and thresholds. Among the 370 patients included, 51 (14%) died within the first 72 h with 40 (11%) EDASS. A strategy in two steps (CDV ≥ 800 μg/kg at 6 h and/or CDV ≥ 2,600 μg/kg at 24 h) was able to predict EDASS with sensitivity of 45%, specificity 97%, positive predictive value 78% and negative predictive value 94%. Overall, our results confirm that early death directly attributable to septic shock could be effectively predicted by the CDV in the first hours of treatment. These results will help to select patients eligible for innovative therapies aimed at improving early mortality in septic shock.
Geospatial mapping can be used to identify geographic areas and social factors associated with intentional injury as targets for prevention efforts distinct to a given community
Authors: Lasecki CH , Mujica FC , Stutsman S , Williams AY , Ding L , Simmons JD , Brevard SB
Published: October 2017

BACKGROUND

Geographic information systems (GIS) have proven effective in studying intentional injury in various communities; however, GIS is not implemented widely for use by Level I trauma centers in understanding patient populations. Our study of intentional injury combines the capabilities of GIS with a Level I trauma center registry to determine the spatial distribution of victims and correlated socioeconomic factors.

METHODS

One thousand ninety-nine of 3,109 total incidents of intentional trauma in the trauma registry from 2005 to 2015 had sufficient street address information to be mapped in GIS. Comparison of these data, coupled with demographic data at the block group level, determined if any clustering or spatial patterns existed. Geographic information systems delivered these comparisons using several spatial statistics including kernel density, ordinary least squares test, and Moran’s index.

RESULTS

Kernel density analysis identified four major areas with significant clustering of incidents. The Moran’s I value was 0.0318. Clustering exhibited a positive z-score and significant p value (p < 0.01). Examination of socioeconomic factors by spatial correlation with the distribution of intentional injury incidents identified three significant factors: unemployment, single-parent households, and lack of a high school degree. Tested factors did not exhibit substantial redundancy (variance inflation factor < 7.5). Nonsignificant tested factors included race, proximity to liquor stores and bars, median household income, per capita income, rate with public assistance, and population density.

CONCLUSION

Spatial representation of trauma registry data using GIS effectively identifies high-risk areas for intentional injury. Analysis of local socioeconomic data identifies factors unique to those high-risk areas in the observed community. Implications of this study may include the routine use of GIS by Level I trauma centers in assessing intentional injury in a given community, the use of that data to guide the development of trauma prevention, and the assessment of other mechanisms of trauma using GIS.

LEVEL OF EVIDENCE

Epidemiological, level IV.
Reexamination of a Battlefield Trauma Golden Hour Policy
Authors: Howard Jeffrey T. , Kotwal Russ S. , Santos-Lazada Alexis R. , Martin Matthew J. , Stockinger Zsolt T.
Published: October 2017

BACKGROUND

Most combat casualties who die, do so in the prehospital setting. Efforts directed toward alleviating prehospital combat trauma death, known as killed in action (KIA) mortality, have the greatest opportunity for eliminating preventable death.

METHODS

Four thousand five hundred forty-two military casualties injured in Afghanistan from September 11, 2001, to March 31, 2014, were included in this retrospective analysis to evaluate proposed explanations for observed KIA reduction after a mandate by Secretary of Defense Robert M. Gates that transport of injured service members occur within 60 minutes. Using inverse probability weighting to account for selection bias, data were analyzed using multivariable logistic regression and simulation analysis to estimate the effects of (1) gradual improvement, (2) damage control resuscitation, (3) harm from inadequate resources, (4) change in wound pattern, and (5) transport time on KIA mortality.

RESULTS

The effect of gradual improvement measured as a time trend was not significant (adjusted odds ratio [AOR], 0.99; 95% confidence interval [CI], 0.94–1.03; p = 0.58). For casualties with military Injury Severity Score of 25 or higher, the odds of KIA mortality were 83% lower for casualties who needed and received prehospital blood transfusion (AOR, 0.17; 95% CI, 0.06–0.51; p = 0.002); 33% lower for casualties receiving initial treatment by forward surgical teams (AOR, 0.67; 95% CI, 0.58–0.78; p < 0.001); 70%, 74%, and 87% lower for casualties with dominant injuries to head (AOR, 0.30; 95% CI, 0.23–0.38; p < 0.001), abdomen (AOR, 0.26, 95% CI, 0.19–0.36; p < 0.001) and extremities (AOR, 0.13; 95% CI, 0.09–0.17; p < 0.001); 35% lower for casualties categorized with blunt injuries (AOR, 0.65; 95% CI, 0.46–0.92; p = 0.01); and 39% lower for casualties transported within one hour (AOR, 0.61; 95% CI, 0.51–0.74; p < 0.001). Results of simulations in which transport times had not changed after the mandate indicate that KIA mortality would have been 1.4% higher than observed, equating to 135 more KIA deaths (95% CI, 105–164).

CONCLUSION

Reduction in KIA mortality is associated with early treatment capabilities, blunt mechanism, select body locations of injury, and rapid transport.

LEVEL OF EVIDENCE

Therapy, level III.
Don’t call me crazy! Delirium occurs outside of the intensive care unit
Authors: Cahill Anthony , Pearcy Christopher , Almahmoud Khalid , Agrawal Vaidehi , Mani Usha , Sladek Phillip , Truitt Michael S.
Published: October 2017

Introduction

Delirium has been well studied among patients in the intensive care unit (ICU); however, data beyond the ICU is limited. The purpose of this study is to prospectively evaluate the incidence and associated risk factors for delirium in noncritical care areas (NCCA).

Methods

After institutional review board approval, a prospective cohort study was conducted at our urban Level I Trauma Center from December 2015 to February 2016. All patients admitted to the designated study area by a trauma surgeon were included. The Confusion Assessment Method (CAM) was administered every 12 hours until discharge. Delirious patients (CAM+) were administered the CAM-S to quantify the severity of delirium. Demographics, laboratory data, and inpatient medication lists were analyzed.

Results

Of 148 participants, 12 (8%) were CAM+ and 136 (92%) were CAM−. The average CAM-S of CAM+ patients was 7 ± 3. Included patients were aged 52 ± 20 years and 45% were men. Of patients 65 years or older, 9 (21%) were CAM+. Medications associated with delirium were: albuterol (p = 0.01), atorvastatin (p = 0.01), duloxetine (p = 0.04), sertraline (p = 0.04), folic acid (p = 0.01), thiamine (p = 0.01), vitamin D (p < 0.001), haloperidol (p = 0.04), metoprolol (p = 0.02), and vancomycin (p = 0.02). Abnormal laboratory values associated with delirium included: Albumin (p = 0.03; odds ratio [OR], 7.94, 95% confidence interval [CI], 1.1–63.20), Calcium (p = 0.01; OR, 4.95; 95% CI, 1.5–16.7), Sodium (p = 0.04; OR, 3.91; 95% CI, 1.13–13.5), hematocrit (p = 0.04), and mean corpuscular hemoglobin concentration (p < 0.05; OR, 5.29; 95% CI, 1.19–23.46).

Conclusions

Our study demonstrated an 8% incidence of delirium overall in NCCA, increasing to 21% in patients 65 years or older. Many risk factors identified among NCCA patients are consistent with the ICU literature; however, our CAM+ patients had additional risk factors which have not been previously associated with the development of delirium. Screening of NCCA patients for delirium should be considered.

Level of Evidence

Prognostic and Epidemological, level IV.
Recent development of nanoparticles for molecular imaging
Authors: Kim Jonghoon , Lee Nohyun , Hyeon Taeghwan
Published: October 2017

Molecular imaging enables us to non-invasively visualize cellular functions and biological processes in living subjects, allowing accurate diagnosis of diseases at early stages. For successful molecular imaging, a suitable contrast agent with high sensitivity is required. To date, various nanoparticles have been developed as contrast agents for medical imaging modalities. In comparison with conventional probes, nanoparticles offer several advantages, including controllable physical properties, facile surface modification and long circulation time. In addition, they can be integrated with various combinations for multimodal imaging and therapy. In this opinion piece, we highlight recent advances and future perspectives of nanomaterials for molecular imaging.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Current status and future challenges for molecular imaging
Authors: Anderson Carolyn J. , Lewis Jason S.
Published: October 2017

Molecular imaging (MI), used in its wider sense of biology at the molecular level, is a field that lies at the intersection of molecular biology and traditional medical imaging. As advances in medicine have exponentially expanded over the last few decades, so has our need to better understand the fundamental behaviour of living organisms in a non-invasive and timely manner. This commentary draws from topics the authors addressed in their presentations at the 2017 Royal Society Meeting ‘Challenges for chemistry in molecular imaging’, as well as a discussion of where MI is today and where it is heading in the future.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Multimodal nanoparticle imaging agents: design and applications
Authors: Burke Benjamin P. , Cawthorne Christopher , Archibald Stephen J.
Published: October 2017

Molecular imaging, where the location of molecules or nanoscale constructs can be tracked in the body to report on disease or biochemical processes, is rapidly expanding to include combined modality or multimodal imaging. No single imaging technique can offer the optimum combination of properties (e.g. resolution, sensitivity, cost, availability). The rapid technological advances in hardware to scan patients, and software to process and fuse images, are pushing the boundaries of novel medical imaging approaches, and hand-in-hand with this is the requirement for advanced and specific multimodal imaging agents. These agents can be detected using a selection from radioisotope, magnetic resonance and optical imaging, among others. Nanoparticles offer great scope in this area as they lend themselves, via facile modification procedures, to act as multifunctional constructs. They have relevance as therapeutics and drug delivery agents that can be tracked by molecular imaging techniques with the particular development of applications in optically guided surgery and as radiosensitizers. There has been a huge amount of research work to produce nanoconstructs for imaging, and the parameters for successful clinical translation and validation of therapeutic applications are now becoming much better understood. It is an exciting time of progress for these agents as their potential is closer to being realized with translation into the clinic. The coming 5–10 years will be critical, as we will see if the predicted improvement in clinical outcomes becomes a reality. Some of the latest advances in combination modality agents are selected and the progression pathway to clinical trials analysed.

This article is part of the themed issue ‘Challenges for chemistry in molecular imaging’.
Using experience to improve: How errors shape behavior and brain activity in monkeys
Authors: Pardo-Vazquez Jose L. , Acuña Carlos
Published: October 2017

Previous works have shown that neurons from the ventral premotor cortex (PMv) represent several elements of perceptual decisions. One of the most striking findings was that, after the outcome of the choice is known, neurons from PMv encode all the information necessary for evaluating the decision process. These results prompted us to suggest that this cortical area could be involved in shaping future behavior. In this work, we have characterized neuronal activity and behavioral performance as a function of the outcome of the previous trial. We found that the outcome of the immediately previous trial (n-1) significantly changes, in the current trial (n), the activity of single cells and behavioral performance. The outcome of trial n-2, however, does not affect either behavior or neuronal activity. Moreover, the outcome of difficult trials had a greater impact on performance and recruited more PMv neurons than the outcome of easy trials. These results give strong support to our suggestion that PMv neurons evaluate the decision process and use this information to modify future behavior.
A Major Role for Common Genetic Variation in Anxiety Disorders
Authors: Purves Kirstin L. , Coleman Jonathan R. I. , Meier Sandra M. , Rayner Christopher , Davis Katrina A. S. , Cheesman Rosa , Bækvad-Hansen Marie , Børglum Anders D. , Cho Shing Wan , Deckert Jürgen , Gaspar Héléna A. , Bybjerg-Grauholm Jonas , Hettema John M. , Hotopf Matthew , Hougaard David , Hübel Christopher , Kan Carol , McIntosh Andrew M. , Mors Ole , Mortensen Preben Bo , Nordentoft Merete , Werge Thomas , Nicodemus Kristin K. , Mattheisen Manuel , Breen Gerome , Eley Thalia C.
Published: October 2017

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (n = 83 565) and an additional Current Anxiety Symptoms (n= 77 125) analysis. The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.
Amplification-free, CRISPR-Cas9 Targeted Enrichment and SMRT Sequencing of Repeat-Expansion Disease Causative Genomic Regions
Authors: Tsai Yu-Chih , Greenberg David , Powell James , Höijer Ida , Ameur Adam , Strahl Maya , Ellis Ethan , Jonasson Inger , Mouro Pinto Ricardo , Wheeler Vanessa C. , Smith Melissa L. , Gyllensten Ulf , Sebra Robert , Korlach Jonas , Clark Tyson A.
Published: October 2017

Targeted sequencing has proven to be an economical means of obtaining sequence information for one or more defined regions of a larger genome. However, most target enrichment methods require amplification. Some genomic regions, such as those with extreme GC content and repetitive sequences, are recalcitrant to faithful amplification. Yet, many human genetic disorders are caused by repeat expansions, including difficult to sequence tandem repeats.

We have developed a novel, amplification-free enrichment technique that employs the CRISPR-Cas9 system for specific targeting multiple genomic loci. This method, in conjunction with long reads generated through Single Molecule, Real-Time (SMRT) sequencing and unbiased coverage, enables enrichment and sequencing of complex genomic regions that cannot be investigated with other technologies. Using human genomic DNA samples, we demonstrate successful targeting of causative loci for Huntington’s disease (HTT; CAG repeat), Fragile X syndrome (FMR1; CGG repeat), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (C9orf72; GGGGCC repeat), and spinocerebellar ataxia type 10 (SCA10) (ATXN10; variable ATTCT repeat). The method, amenable to multiplexing across multiple genomic loci, uses an amplification-free approach that facilitates the isolation of hundreds of individual on-target molecules in a single SMRT Cell and accurate sequencing through long repeat stretches, regardless of extreme GC percent or sequence complexity content. Our novel targeted sequencing method opens new doors to genomic analyses independent of PCR amplification that will facilitate the study of repeat expansion disorders.
Non-invasive detection of upper tract urothelial carcinomas through the analysis of driver gene mutations and aneuploidy in urine
Authors: Springer Simeon , Chen Chung-Hsin , Li Lu , Douville Chris , Wang Yuxuan , Cohen Josh , Afsari Bahman , Danilova Ludmila , Silliman Natalie , Schaeffer Joy , Ptak Janine , Dobbyn Lisa , Papoli Maria , Kinde Isaac , Huang Chao-Yuan , Shun Chia-Tung , Karchin Rachel , Netto George J. , Turesky Robert J. , Yun Byeong Hwa , Rosenquist Thomas A. , Hruban Ralph H. , Pu Yeong-Shiau , Grollman Arthur P. , Tomasetti Cristian , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Dickman Kathleen G.
Published: October 2017

Upper tract urothelial carcinomas (UTUC) of the renal pelvis or ureter can be difficult to detect and challenging to diagnose. Here, we report the development and application of a non-invasive test for UTUC based on molecular analyses of DNA recovered from cells shed into the urine. The test, called UroSEEK, incorporates assays for mutations in eleven genes frequently mutated in urologic malignancies and for allelic imbalances on 39 chromosome arms. At least one genetic abnormality was detected in 75% of urinary cell samples from 56 UTUC patients but in only 0.5% of 188 samples from healthy individuals. The assay was considerably more sensitive than urine cytology, the current standard-of-care. UroSEEK therefore has the potential to be used for screening or to aid in diagnosis in patients at increased risk for UTUC, such as those exposed to herbal remedies containing the carcinogen aristolochic acid.
p53 suppresses mutagenic RAD52 and POLθ pathways by orchestrating DNA replication restart homeostasis
Authors: Roy Sunetra , Tomaszowski Karl-Heinz , Luzwick Jessica , Park Soyoung , Li Jun , Murphy Maureen , Schlacher Katharina
Published: October 2017

Classically, p53 tumor-suppressor acts in transcription, apoptosis, and cell-cycle arrest. Yet, replication-mediated genomic instability is integral to oncogenesis, and p53 mutations promote tumor progression and drug-resistance. By delineating human and murine separation-of-function p53 alleles, we find that p53 null and gain-of-function (GOF) mutations exhibit defects in restart of stalled or damaged DNA replication forks driving genomic instability independent of transcription activation. By assaying protein-DNA fork interactions in single cells, we unveil a p53-MLL3-enabled recruitment of MRE11 DNA replication restart nuclease. Importantly, p53 defects or depletion unexpectedly allow mutagenic RAD52 and POLθ pathways to hijack stalled forks, which we find reflected in p53 defective breast-cancer patient COSMIC mutational signatures. These data uncover p53 as a keystone regulator of replication homeostasis within a DNA restart network. Mechanistically, this has important implications for development of resistance in cancer therapy. Combined, these results define an unexpected role for p53 suppression of replication genome instability.
highroadis induced by retinoids and clears mutant Rhodopsin-1 inDrosophilaRetinitis Pigmentosa models
Authors: Huang Huai-Wei , Brown Brian , Chung Jaehoon , Domingos Pedro M. , Ryoo Hyung Don
Published: October 2017

The light detecting protein, Rhodopsin, requires retinoid chromophores for their function. In vertebrates, retinoids also serve as signaling molecules, but whether these molecules similarly regulate gene expression inDrosophilaremains unclear. Here, we report the identification of a retinoid-inducible gene inDrosophila,highroad, which is required for photoreceptors to clear folding-defective mutant Rhodopsin-1 proteins. Specifically, we identifiedhighroadthrough an in vivo RNAi based genetic interaction screen with one such folding defective Rhodopsin-1 mutant,ninaEG69D. CRISPR-Cas9-mediated deletion ofhighroadresults in the stabilization of folding-defective mutant Rhodopsin-1 proteins, and acceleration of the age-related retinal degeneration phenotype ofninaEG69Dmutants. Elevatedhighroadtranscript levels are detectedninaEG69Dflies, and interestingly, deprivation of retinoids in the fly diet blocks this effect. Consistently, mutations in the retinoid transportersanta mariaimpairs the induction ofhighroadinninaEG69Dflies. In cultured S2 cells,highroadexpression is induced by retinoic acid treatment. These results indicate that cellular quality control mechanism against misfolded Rhodopsin-1 involves regulation of gene expression by retinoids.
Enhanced wort fermentation withde novolager hybrids adapted to high ethanol environments
Authors: Krogerus Kristoffer , Holmström Sami , Gibson Brian
Published: October 2017

Interspecific hybridization is a valuable tool for developing and improving brewing yeast in a number of industry-relevant aspects. However, the genomes of newly formed hybrids can be unstable. Here, we exploited this trait by adapting four brewing yeast strains, three of which werede novointerspecific lager hybrids with different ploidy levels, to high ethanol concentrations in an attempt to generate variant strains with improved fermentation performance in high-gravity wort. Through a batch fermentation-based adaptation process and selection based on a two-step screening process, we obtained eight variant strains which we compared to the wild-type strains in 2L-scale wort fermentations replicating industrial conditions. The results revealed that the adapted variants outperformed the strains from which they were derived, and the majority also possessed several desirable brewing-relevant traits, such as increased ester formation and ethanol tolerance, as well as decreased diacetyl formation. The variants obtained from the polyploid hybrids appeared to show greater improvements in fermentation performance. Interestingly, it was not only the hybrid strains, but also theS. cerevisiaeparent strain, that appeared to adapt and showed considerable changes in genome size. Genome sequencing and ploidy analysis revealed that changes had occurred both at chromosome and single nucleotide level in all variants. Our study demonstrates the possibility of improvingde novolager yeast hybrids through adaptive evolution by generating stable and superior variants that possess traits relevant to industrial lager beer fermentation.

Importance

Recent studies have shown that hybridization is a valuable tool for creating new and diverse strains of lager yeast. Adaptive evolution is another strain development tool that can be applied in order to improve upon desirable traits. Here we apply adaptive evolution to newly created lager yeast hybrids by subjecting them to environments containing high ethanol levels. We isolate and characterize a number of adapted variants, which possess improved fermentation properties and ethanol tolerance. Genome analysis revealed substantial changes in the variants compared to the original strains. These improved variants strains were produced without any genetic modification, and are suitable for industrial lager beer fermentations.
Transcranial alternating current stimulation induces long-term augmentation of neural connectivity and sustained anxiety reduction
Authors: Clancy Kevin J. , Baisley Sarah K. , Albizu Alejandro , Kartvelishvili Nicholas , Ding Mingzhou , Li Wen
Published: October 2017

Although transcranial alternating current stimulation (tACS) has demonstrated short-term effects in modulating neural oscillations, potential clinical efficacy of tACS for treating “oscillopathies” (disorders associated with aberrant neural oscillations) hinges on its ability to generate long-term neural plasticity, which can translate into lasting behavioral changes. Administering alpha-frequency tACS over 4 consecutive days, we evaluated short- and long-term (> 24 hours) effects of α-tACS on local alpha power and oscillatory connectivity, along with behavioral outcomes in anxious arousal and affective sensory perception. The α-tACS (vs. sham stimulation) group exhibited increases in posterior alpha power immediately and 30 minutes post-stimulation but not 24 hours post-stimulation, suggesting transient effects on local neuronal synchrony. Strikingly, long-range alpha-frequency Granger causal connectivity (posterior→frontal) increased not only immediately and 30 minutes but also 24 hours post-stimulation, paralleled by sustained reductions in anxious arousal and aversion to auditory stimuli. Therefore, tACS is capable of eliciting long-term plasticity in long-range oscillatory connectivity with direct, lasting behavioral consequences, while leaving endogenous local oscillations unaltered. This temporal disparity in local and network effects favors the view of large-scale network strengthening by tACS, calling for research attention to the circuit and network impacts of tACS. Critically, with the growing recognition of large-scale network dysfunctions as a transdiagnostic pathophysiology of psychiatric disorders, this connectivity plasticity advocates for the clinical application of tACS with its unique advantage in tackling network pathologies.
A class of GATA3 mutation reprograms the breast cancer transcriptional network through gain and loss of function
Authors: Takaku Motoki , Grimm Sara A. , Roberts John D. , Chrysovergis Kaliopi , Bennett Brian D. , Myers Page , Perera Lalith , Tucker Charles J. , Perou Charles M. , Wade Paul A.
Published: October 2017

GATA3 is frequently mutated in breast cancer; these mutations are widely presumed to be loss of function. Here, we address molecular alterations downstream of a novel class of GATA3 mutations, revealing both gain and loss of function. Mutation of one allele of GATA3 led to loss of binding and decreased expression at a subset of genes, including Progesterone Receptor. At other loci, associated with epithelial to mesenchymal transition, gain of binding at a novel sequence motif correlated with increased gene expression. These results demonstrate that not all GATA3 mutations are equivalent and that these mutations impact breast cancer through gain and loss of function.
Assessing bimanual motor skills with optical neuroimaging
Authors: Nemani Arun , Yucel Meryem , Kruger Uwe , Gee Denise , Cooper Clairice , Schwaitzberg Steven , De Suvranu , Intes Xavier
Published: October 2017

Measuring motor skill proficiency is critical for the certification of highly-skilled individuals in numerous fields. However, conventional measures use subjective metrics that often cannot distinguish between expertise levels. Here, we present an advanced optical neuroimaging methodology that can objectively and successfully classify subjects with different expertise levels associated with bimanual motor dexterity. The methodology was tested by assessing laparoscopic surgery skills within the framework of the fundamentals of laparoscopic surgery program, which is a pre-requisite for certification in general surgery. We demonstrate that optical-based metrics outperformed current metrics for surgical certification in classifying subjects with varying surgical expertise. Moreover, we report that optical neuroimaging allows for the successful classification of subjects during the acquisition of such skills.
Efficient generation of targeted large insertions in mouse embryos using 2C-HR-CRISPR
Authors: Gu Bin , Posfai Eszter , Rossant Janet
Published: October 2017

Rapid and efficient generation of large fragment targeted knock-in mouse models is still a major hurdle in mouse genetics. Here we developed 2C-HR-CRISPR, a highly efficient gene editing method based on introducing CRISPR reagents into mouse embryos at the 2-cell stage, taking advantage of the likely increase in HR efficiency during the long G2 phase and open chromatin structure of the 2-cell embryo. With 2C-HR-CRISPR and a modified biotin-streptavidin approach to localize repair templates to target sites, we rapidly targeted 20 endogenous genes that are expressed in mouse blastocysts with fluorescent reporters and generated reporter mouse lines. We showcase the first live triple-color blastocyst with all three lineages differentially reported. Additionally, we demonstrated efficient double targeting, enabling rapid assessment of the auxin-inducible degradation system for probing protein function in mouse embryos. These methods open up exciting avenues for exploring cell fate decisions in the blastocyst and later stages of development. We also suggest that 2C-HR-CRISPR can be a better alternative to random transgenesis by ensuring transgene insertions at defined ‘safe harbor’ sites.
Post-training reversible disconnection of the ventral hippocampal–basolateral amygdaloid circuits impairs consolidation of inhibitory avoidance memory in rats
Authors: Wang Gong-Wu , Liu Jian , Wang Xiao-Qin
Published: October 2017

The ventral hippocampus (VH) and the basolateral amygdala (BLA) are both crucial in inhibitory avoidance (IA) memory. However, the exact role of the VH–BLA circuit in IA memory consolidation is unclear. This study investigated the effect of post-training reversible disconnection of the VH–BLA circuit in IA memory consolidation. Male Wistar rats with implanted guide cannulae were trained with a one-trial IA task, then received immediate intracerebral injections of muscimol or saline, and were tested 24 h later. Muscimol injection into the bilateral BLA, or the unilateral VH and contralateral BLA, but not the unilateral VH and ipsilateral BLA, significantly decreased the retention latencies (versus saline treatment). The results suggest that the VH–BLA circuit could be an important circuit to modulate consolidation of IA memory in rats.
The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala
Authors: Temme Stephanie J. , Murphy Geoffrey G.
Published: October 2017

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, CaV1.2 and CaV1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the CaV1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of CaV1.2 in all neuronal populations, we generated CaV1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of CaV1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of CaV1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically CaV1.2, in extinction learning. Further exploration on the effects of deletion of CaV1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of CaV1.2 in fear extinction and the synaptic regulation of activity within the amygdala.
Hippocampal area CA1 and remote memory in rats
Authors: Ocampo Amber C. , Squire Larry R. , Clark Robert E.
Published: October 2017

Hippocampal lesions often produce temporally graded retrograde amnesia (TGRA), whereby recent memory is impaired more than remote memory. This finding has provided support for the process of systems consolidation. However, temporally graded memory impairment has not been observed with the watermaze task, and the findings have been inconsistent with context fear conditioning. One possibility is that large hippocampal lesions indirectly disrupt (by retrograde degeneration) the function of areas that project to the hippocampus that are important for task performance or thought to be important for storing consolidated memories. We developed a discrete lesion targeting area CA1, the sole output of the hippocampus to neocortex, and tested the effects of this lesion on recent and remote memory in the watermaze task, in context fear conditioning, and in trace fear conditioning. In all three tasks, recent and remote memory were similarly impaired after CA1 lesions. We discuss factors that help to illuminate these findings and consider their relevance to systems consolidation.
GigaFRoST: the gigabit fast readout system for tomography
Authors: Mokso Rajmund , Schlepütz Christian M. , Theidel Gerd , Billich Heiner , Schmid Elmar , Celcer Tine , Mikuljan Gordan , Sala Leonardo , Marone Federica , Schlumpf Nick , Stampanoni Marco
Published: October 2017

Owing to recent developments in CMOS technology, it is now possible to exploit tomographic microscopy at third-generation synchrotron facilities with unprecedented speeds. Despite this rapid technical progress, one crucial limitation for the investigation of realistic dynamic systems has remained: a generally short total acquisition time at high frame rates due to the limited internal memory of available detectors. To address and solve this shortcoming, a new detection and readout system, coined GigaFRoST, has been developed based on a commercial CMOS sensor, acquiring and streaming data continuously at 7.7 GB s−1directly to a dedicated backend server. This architecture allows for dynamic data pre-processing as well as data reduction, an increasingly indispensable step considering the vast amounts of data acquired in typical fast tomographic experiments at synchrotron beamlines (up to several tens of TByte per day of raw data).
Side-chain conformations in the isomorphous polyfluorinated {4,4′-bis[(2,2-difluoroethoxy)methyl]-2,2′-bipyridine-κ2
N,N′}dichloridopalladium and -platinum complexes
Authors: Lu Norman , Zheng Jing-Hung , Lu Yi-Jing , Chiang Hsing-Fang , Chu Chun-Wei , Thrasher Joseph S. , Wen Yuh-Sheng , Liu Ling-Kang
Published: October 2017

The polyfluorinated title compounds, [MCl2(C16H16F4N2O2)] or [4,4′-(HCF2CH2OCH2)2-2,2′-bpy]MCl2 [M = Pd, (1), and M = Pt, (2)], have –C(Hα)2OC(Hβ)2CF2H side chains with H-atom donors at the α and β sites. The structures of (1) and (2) are isomorphous, with the nearly planar (bpy)MCl2 molecules stacked in columns. Within one column, π-dimer pairs alternate between a π-dimer pair reinforced with C—H...Cl hydrogen bonds (α,α) and a π-dimer pair reinforced with C—Hβ...F(—C) interactions (abbreviated as C—Hβ...F—C,C—Hβ...F—C). The compounds [4,4′-(CF3CH2OCH2)2-2,2′-bpy]MCl2 [M = Pd, (3), and M = Pt, (4)] have been reported to be isomorphous [Lu et al. (2012). J. Fluorine Chem.
137, 54–56], yet with disorder in the fluorous regions. The molecules of (3) [or (4)] also form similar stacks, but with alternating π-dimer pairs between the (α,β; α,β) and (β,β) forms. Through (C—)H...Cl hydrogen-bond interactions, one molecule of (1) [or (2)] is expanded into an aggregate of two inversion-related π-dimer pairs, one pair in the (α,α) form and the other pair in the (C—Hβ...F—C,C—Hβ...F—C) form, with the plane normals making an interplanar angle of 58.24 (3)°. Due to the demands of maintaining a high coordination number around the metal-bound Cl atoms in molecule (1) [or (2)], the ponytails of molecule (1) [or (2)] bend outward; in contrast, the ponytails of molecule (3) [or (4)] bend inward.
Extrinsic faulting in 3Cclose-packed crystal structures: computational mechanics analysis
Authors: Estevez-Rams Ernesto , Lora-Serrano Raimundo , Penton-Madrigal Arbelio , Nespolo Massimo
Published: October 2017

Extrinsic faulting has been discussed previously within the so-called difference method and random walk calculation. In this contribution it is revisited under the framework of computational mechanics, which allows expressions to be derived for the statistical complexity, entropy density and excess entropy as a function of faulting probability. The approach allows one to compare the disordering process of an extrinsic fault with other faulting types. The ∊-machine description of the faulting mechanics is presented. Several useful analytical expressions such as probability of consecutive symbols in the Hägg coding are presented, as well as hexagonality. The analytical expression for the pairwise correlation function of the layers is derived and compared with results previously reported. The effect of faulting on the interference function is discussed in relation to the diffraction pattern.
Development and validation of the team influence relations scale (TIReS)
Authors: Kozusznik Barbara , Paliga Mateusz , Smorczewska Barbara , Grabowski Damian , Kozusznik Malgorzata Wanda
Published: October 2017

Purpose

The purpose of this paper is to develop and validate the Team Influence Relations Scale (TIReS), a new instrument to measure the relation of influence in a team that overcomes a predominating individual approach to influence in teams. The TIReS stems from the concepts of team subjectivity and deinfluentization that perceive influence as a collective phenomenon in a triangular influence model.

Design/methodology/approach

In the first study the authors subjected the data, gathered from 280 employees from Polish private sector companies, to the principal axis factoring analysis, yielding 12 best-fitting items loading on two factors (i.e. meaning reduction and space offering). In the second study the authors employed confirmatory factor analyses to test data from 784 workers from private sector organizations in Poland.

Findings

The results yielded a six-factor structure for the TIReS (root mean square error of approximation=0.077, comparative fit index=0.93, NNFI=0.91, standardized root mean square residual=0.073) with two sub-dimensions for each influence source in a team (i.e. the individual, the leader, the team as a whole). The results provide evidence for the internal consistency reliability of the TIReS (Cronbach’s α ranging from 0.87 to 0.93 for TIReS factors) and its satisfactory criterion-related validity.

Originality/value

The TIReS addresses a gap in currently available questionnaires to measure the relation of influence in teams considering three sources of influence in a team. The importance of team influence relations measurement is discussed.
Fears, discrimination and perceived workplace promotion
Authors: Sheaffer Zachary , Levy Shalom , Navot Edo
Published: October 2017

Purpose

Past research about workplace promotion has focussed on factors that shape employees’ perceptions for promotion. Yet, we still know little about how such undesirable factors as the fear of success (henceforth FoS) syndrome and perceived workplace discrimination affect perceived promotion and even less so how this relationship is mediated by self-efficacy and intrinsic motivation. The purpose of this paper is to propose a conceptual framework integrating these factors.

Design/methodology/approach

A structural equation modelling procedure was employed to empirically test the model using data collected from employees in wide-ranging Israeli industries (n=553).

Findings

The path model indicates that initially, FoS and perceived discrimination negatively affect perceived chances of promotion. When however, self-efficacy and intrinsic motivation mediate this relationship, subjects perceive their promotion chances positively.

Practical implications

Self-efficacy and intrinsic motivation may be employed to attenuate the potentially adverse effects of FoS and discrimination effects.

Originality/value

FoS and perceived workplace discrimination are common phenomena, yet the authors show that they may be mitigated by heightened self-efficacy and amplified intrinsic motivation that help in sustaining perceived workplace promotion.