bluuebunny/crossref_metadata_2025 huggingface dataset:
Capillary Electrochromatography: A Powerful Tool for the Resolution of Complex Mixtures
Authors: Vallano Patrick T , Remcho Vincent T
Published: February 2020

Methods such as capillary electrophoresis (CE) and capillary liquid chromatography (LC) are particularly useful in the analysis of complex mixtures because of their high resolving power. Continued refinement of these techniques has led to a novel separation method known as capillary electrochromatography (CEC), also referred to as capillary electrokinetic chromatography, which is a combination of capillary LC and conventional CE. As in LC, mobile phase is transported through a column where partitioning of solutes occurs. In CEC, mobile phase flow is generated by electroosmosis, which arises when an electric potential is applied across the long axis of the capillary column. The favorable flow dynamics of electroosmosis result in higher chromatographic efficiencies in CEC relative to LC. If the species of interest are charged, a second separation mechanism is afforded by electrophoresis. CEC combines the high efficiency of capillary electrophoretic separations with the broad range of selectivity obtainable in LC. As such, CEC provides numerous advantages over other separation methods. This study introduces the theory, principles, instrumentation, and applications of this technique.
‘Simple photograph’ or work of art? Well-known image of Judges Falcone and Borsellino deemed insufficiently creative for protection under Article 2 of the Italian Copyright Act
Authors: Mancinella Matteo
Published: February 2020

Rome Court of First Instance, 17th Civil Section specialized in enterprise matters, decision on 12 September 2019, No. 14758

The Rome Court of First Instance ruled that a well-known photograph depicting the Italian judges Falcone and Borsellino, relaxed and smiling during a conference in Palermo on 27 March 1992, does not fall within the scope of protection of Article 2 of the Italian Copyright Act because it is not characterized by sufficient creativity and because its author did not have an artistic objective in mind a priori.
The Marlowe corpus revisited
Authors: Ilsemann Hartmut
Published: February 2020

Following Dr Barber’s unfortunate criticism (Barber, 2018, Marlowe and overreaching: a misuse of stylometry. Digital Scholarship in the Humanities, 34: 1–12), in which she, with an obvious lack of familiarity with them, subjected the Rolling Delta procedures used, to the caveats of Delta and traditional stylometry, this article makes use of an extended methodological framework and applies Rolling Delta to the target texts with a totality of reference texts. The outcome is different from the expected, since the author of Tamburlaine 1 and 2 emerges as stylistically also dominant in the anonymous play The Tragedy of Locrine, in Kyd’s closet play Cornelia, in Peele’s The Battle of Alcazar and David and Bethsabe. In contrast, the official Marlowe corpus relates stylistically to contemporary authors, but not to the two Tamburlaines. Traditional scholarship and learning do not refute conjectures of misattributed Peele plays and there are also strong indications that plays associated with Lord Strange’s Men nominally became Marlowe plays when Henslowe acquired them in 1594 for his Admiral’s Men and printers made use of the cult of personality, in which the author’s death became an important factor in the marketing of printed playbooks. Otherwise, there is no documentary and empirical evidence that Marlowe wrote the plays in question. The canonization of the plays occurred only in the nineteenth century, and the Marlowe we have inherited—the poet, spy, atheist, homosexual, and so on—is almost entirely an invention of the twentieth century (Hooks, 2018, Making Marlowe. In Melnikoff, K. and Knutson, R. (eds), Christopher Marlowe, Theatrical Commerce, and the Book Trade. Cambridge: University Press, p. 98).
Outflows in star-forming galaxies: Stacking analyses of resolved winds and the relation to their hosts’ properties
Authors: Roberts-Borsani G W , Saintonge A , Masters K L , Stark D V
Published: February 2020

Outflows form an integral component in regulating the gas cycling in and out of galaxies, although their impact on the galaxy hosts is still poorly understood. Here we present an analysis of 405 high mass (log M*/M⊙ ≥ 10), star-forming galaxies (excluding AGN) with low inclinations at z ∼ 0, using stacking techniques of the Na D λλ5889, 5895 Å neutral gas tracer in IFU observations from the MaNGA DR15 survey. We detect outflows in the central regions of 78/405 galaxies and determine their extent and power through the construction of stacked annuli. We find outflows are most powerful in central regions and extend out to ∼1Re, with declining mass outflow rates and loading factors as a function of radius. The stacking of spaxels over key galaxy quantities reveals outflow detections in regions of high ΣSFR (≳0.01 M⊙ yr−1 kpc−2) and $\Sigma _{M_{*}}$ (≳107 M⊙ kpc−2) along the resolved main sequence. Clear correlations with ΣSFR suggest it is the main regulator of outflows, with a critical threshold of ∼0.01 M⊙ yr−1 kpc−2 needed to escape the weight of the disc and launch them. Furthermore, measurements of the Hδ and Dn4000 indices reveal virtually identical star formation histories between galaxies with outflows and those without. Finally, through stacking of H i 21 cm observations for a subset of our sample, we find outflow galaxies show reduced H i gas fractions at central velocities compared to their non-detection control counterparts, suggestive of some removal of H i gas, likely in the central regions of the galaxies, but not enough to completely quench the host.
Understanding divergent domestication traits from the whole-genome sequencing of swamp- and river-buffalo populations
Authors: Luo Xier , Zhou Yu , Zhang Bing , Zhang Yi , Wang Xiaobo , Feng Tong , Li Zhipeng , Cui Kuiqing , Wang Zhiqiang , Luo Chan , Li Hui , Deng Yanfei , Lu Fenghua , Han Jianlin , Miao Yongwang , Mao Huaming , Yi Xiaoyan , Ai Cheng , Wu Shigang , Li Alun , Wu Zhichao , Zhuo Zijun , Da Giang Do , Mitra Bikash , Vahidi Mohammad Farhad , Mansoor Shahid , Al-Bayatti Sahar Ahmed , Sari Eka Meutia , Gorkhali Neena Amatya , Prastowo Sigit , Shafique Laiba , Ye Guoyou , Qian Qian , Chen Baoshan , Shi Deshun , Ruan Jue , Liu Qingyou
Published: February 2020

Domesticated buffaloes have been integral to rice-paddy agro-ecosystems for millennia, yet relatively little is known about the buffalo genomics. Here, we sequenced and assembled reference genomes for both swamp and river buffaloes and we re-sequenced 230 individuals (132 swamp buffaloes and 98 river buffaloes) sampled from across Asia and Europe. Beyond the many actionable insights that our study revealed about the domestication, basic physiology and breeding of buffalo, we made the striking discovery that the divergent domestication traits between swamp and river buffaloes can be explained with recent selections of genes on social behavior, digestion metabolism, strengths and milk production.
Finite-N corrections to the superconformal index of toric quiver gauge theories
Authors: Arai Reona , Fujiwara Shota , Imamura Yosuke , Mori Tatsuya
Published: February 2020

The superconformal index of quiver gauge theories realized on D3-branes in toric Calabi–Yau cones is investigated. We use the AdS/CFT correspondence and study D3-branes wrapped on supersymmetric cycles. We focus on brane configurations in which a single D3-brane is wrapped on a cycle, and we do not take account of branes with multiple wrapping. We propose a formula that gives finite-$N$ corrections to the index caused by such brane configurations. We compare the predictions of the formula for several examples with the results on the gauge theory side obtained by using localization for small sizes of gauge groups, and confirm that the formula correctly reproduces the finite-$N$ corrections up to the expected order.
Inside the black box: credibility and the situational power of central banks
Authors: Zayim Ayca
Published: February 2020

Despite the consensus that the power of finance constraints central banks under financial globalization, the variation in their autonomy from market forces at the micro level of monetary policymaking remains underexplored. This article demonstrates that credibility endows central banks with situational power to make monetary policy decisions that involve less sacrifice of economic growth to price stability. Based on the comparative analysis of the policy decisions of central banks in two emerging economies, South Africa and Turkey, during 2013–2014, I show that this policy space stems from central banks’ capacity to successfully influence market expectations. The argument relies on public texts and over 130 interviews with central bankers in South Africa and Turkey and financiers in Johannesburg, Istanbul and London. The findings contribute to literature on central bank credibility and communication by exploring how credibility functions and creates room for central banks to maneuver through influencing contingent and performative expectations.
The Effect of Pressure Injury Training for Nurses: A Systematic Review and Meta-analysis
Authors: Kim Gaeun , Park Mikyung , Kim Kyungwon
Published: February 2020

OBJECTIVE

To conduct a meta-analysis of the literature on training programs that aimed to improve nurses’ pressure injury management skills.

METHODS

Literature searches were conducted using Ovid-MEDLINE, Cochrane Library, CINAHL, and Korean databases. The search terms used were: (nurse* AND ((pressure OR decubitus) AND (ulcer* OR injur*)) OR bed sore OR bedsore OR decubitus) AND (program* OR training)). Random-effects models were used to calculate the standardized mean difference and odds ratios, with 95% confidence intervals (CIs) to analyze the effects.

MAIN RESULTS

Initial searches yielded 1,067 studies. Of these, 23 met the selection criteria. Nurses’ knowledge (standard mean difference, 1.23; 95% CI, 0.50-1.96; P < .001), visual discrimination ability (standard mean difference, 1.13; 95% CI, 0.88-1.38; P < .001), and clinical judgment (odds ratio, 1.52; 95% CI, 1.46-1.57; P < .001) improved after the programs.

CONCLUSIONS

Pressure injury training programs can improve nurses’ competency. The results from this study indicate that such programs may help improve nurses’ knowledge, visual discrimination ability, and clinical judgment and can be considered continuing education programs. However, large-scale studies are needed to confirm this conclusion.
Data Driven Analysis Reveals Shared Transcriptome Response, Immune Cell Composition, and Distinct Mortality Rates Across Differing Etiologies of Critical Illness
Authors: Zador Zsolt , Landry Alexander , Balas Michael , Marshall John C. , Cusimano Michael D.
Published: February 2020

Objectives:

Sepsis and trauma are common health problems and provide great challenges in critical care. Diverse patient responses to these conditions further complicate patient management and outcome prediction. Whole blood transcriptomics provides a unique opportunity to follow the molecular response in the critically ill. Prior results show robust and diverse genomic signal in the acute phase and others have found shared biological mechanisms across divergent disease etiologies. We hypothesize that selected transcriptomics responses, particularly immune mechanisms are shared across disease etiologies. We further hypothesize that these processes may identify homogenous patient subgroups with shared clinical course in critical illness deciphering disease heterogeneity. These processes may serve as universal markers for predicting a complicated clinical course and/or risk of a poor outcome.

Design:

We present a system level, data driven, genome-wide analysis of whole blood gene expression for a total of 382 patients suffering from either abdominal sepsis (49), pulmonary sepsis (107) or trauma (158) and compare these to gene expression in healthy controls (68).

Patients and Setting:

We relied on available open genetic data from gene expression omnibus for patients diagnosed with abdominal sepsis, community-acquired pneumonia, or trauma which also included healthy control patients.

Measurements and Main Results:

Our results confirm that immune processes are shared across disease etiologies in critical illnesses. We identify two consistent and distinct patient subgroups through deconvolution of serum transcriptomics: 1) increased neutrophils and naïve CD4 cell fractions and 2) suppressed neutrophil fraction. Furthermore, we found immune and inflammatory processes were downregulated in subgroup 2, a configuration previously shown to be more susceptible to multiple organ failure. Correspondingly, this subgroup had significantly higher mortality rates in all three etiologies of illness (0% vs 6.1%,p= 3.1 × 10–39for trauma; 15.0% vs 25.4%,p= 4.4 × 10–9for community-acquired pneumonia, and 7.1% vs 20.0%,p= 3.4 × 10–7for abdominal sepsis).

Conclusions:

We identify two consistent subgroups of critical illness based on serum transcriptomics and derived immune cell fractions, with significantly different survival rates. This may serve as a universal predictor of complicated clinical course or treatment response and, importantly, may identify opportunities for subgroup-specific immunomodulatory intervention.
PEG-LEG ARTERIOLES: AN ADAPTATION TO CHRONIC RETINAL HYPOPERFUSION
Authors: Pollock Stephen C.
Published: February 2020

Purpose:

To describe a heretofore unreported retinal vascular sign related to chronic retinal hypoperfusion.

Methods:

A case report of a 42-year-old woman who was found to have a novel pattern of retinal vascular remodeling in the setting of severe bilateral occlusive disease of the carotid and vertebral arteries.

Results:

The patient had a childhood history of nasopharyngeal carcinoma, treated with external beam radiation. At age 35, she suffered bilateral occipital infarctions. A cerebral angiogram showed complete occlusion of both common carotid arteries and complete occlusion of the proximal segments of both vertebral arteries. Seven years after her stroke, examination of her fundus revealed a remarkable pattern of vascular remodeling that involved nearly all of the major retinal arterioles in both eyes. In each vessel, a narrowed proximal segment abruptly dilated to a larger-than-normal caliber at a distance of 1 to 2 disk diameters from the optic disk. The abnormally increased caliber extended into the retinal periphery.

Conclusion:

Chronic severe retinal hypoperfusion due to profound carotid occlusive disease can lead to adaptive remodeling of the retinal vasculature in a pattern that closely resembles the iconic image of a pirate's peg leg.
Impact of Daptomycin Minimum Inhibitory Concentration on Clinical Cure Rates for Vancomycin-Resistant Enterococcus Infections
Authors: Shah Sunish , Bandali Aiman , Pontiggia Laura , Bias Tiffany E.
Published: February 2020

Purpose

Vancomycin-resistant Enterococcus (VRE) infections are designated a serious threat. Recently, the Clinical and Laboratory Standards Institute revised daptomycin breakpoints for Enterococcus faecium infections to reflect a minimum inhibitory concentration (MIC) of less than 4 mg/L as susceptible dose dependent and 8 mg/L or greater as resistant. The objective was to compare clinical outcomes for patients who had a VRE bloodstream infection (BSI) and a daptomycin MIC of 2 mg/L or greater (low MIC group) versus a daptomycin MIC of 3 to 4 mg/L (high MIC group).

Methods

This was a single-center, retrospective study of adult patients receiving 48 hours or more of daptomycin therapy. The following primary and secondary outcomes were assessed: microbiological cure, clinical cure, and 30-day all-cause mortality.

Results

Sixty-five patients were included in this analysis: 16 patients in the low MIC group and 49 in the high MIC group. Patients in the high MIC group received a longer duration of therapy (14.0 vs 7.5 days, P = 0.047), had a larger percentage of patients receiving concomitant antimicrobials (85.7% vs. 56.2%, P = 0.013), and were more likely to be infected with E. faecium (98.0% vs 56.2%, P < 0.001) compared with the low MIC group. Patients in the low MIC group had a significantly higher clinical cure rate (69.0% vs 31.0%, P = 0.009), microbiological cure rate (100.0% vs. 73.0%, P = 0.027), and a comparable 30-day all-cause mortality rate (19.0% vs 41.0%, P = 0.139) compared with the high MIC group.

Conclusions

High daptomycin MICs were associated with worse outcomes in our patient cohort with VRE BSIs.
Masters Athlete Screening Study (MASS): Insights Into the Psychological Impact of Cardiovascular Preparticipation Screening
Authors: Morrison Barbara N. , Zwaiman Ingrid , Isserow Saul , Taunton Jack , MacDonald Mackenzie , Cater Carlee , Velghe Jane , Hirsch Aliza , Warburton Darren E. R. , McKinney James
Published: February 2020

Objective:

To determine the psychological impact of a cardiovascular disease (CVD) diagnosis identified during preparticipation screening (PPS) of masters athletes.

Design:

Cross-sectional study.

Setting:

Masters athletes diagnosed with CVD through the Masters Athletes Screening Study.

Participants:

Sixty-seven athletes (89.6% male, mean age at diagnosis 60.1 ± 7.1 years, range 40-76) with diagnoses of coronary artery disease (CAD) (73.1%), high premature ventricular contraction burden (9.0%), mitral valve prolapse (7.5%), atrial fibrillation (AF) (3.0%), bicuspid aortic valve (3.0%), aortic dilatation (1.5%), coronary anomaly (1.5%), and rheumatic heart disease (1.5%). Three participants had multiple diagnoses.

Intervention:

Online survey distributed to masters athletes identified with CVD.

Main Outcome Measures:

Assessment of psychological distress [Impact of Event Scale-Revised (IES-R)], perceptions of screening, and preferred support by CVD type.

Results:

The median total IES-R and subscale scores were within the normal range {median [interquartile range (IQR)] total 2.0 [0-6.0]; intrusion 1.0 [0-3.0]; avoidance 0 [0-3.0]; hyperarousal 0 [0-1.0]}. Athletes with bicuspid aortic valve [20.5 (IQR, 4.0-37.0)], AF [7.0 (IQR, 0-14.0)], and severe CAD [5.5 (IQR, 1.0-12.0)] had the highest total IES-R scores. One individual with bicuspid aortic valve reported a significant stress reaction. Ten athletes (14.9%) had scores >12. Ninety-three percent of athletes were satisfied having undergone PPS. Preferred type of support varied by cardiovascular diagnosis.

Conclusions:

The majority of masters athletes diagnosed with CVD through PPS do not experience significant levels of psychological distress. Athletes diagnosed with more severe types of CVD should be monitored for psychological distress. Support should be provided through a multidisciplinary and individualized approach.
The Association of 5α-Reductase Inhibitor With Suicidality
Authors: Kim Jihoon A. , Choi Daein , Choi Seulggie , Chang Jooyoung , Park Sang Min
Published: February 2020

Objective

Using a large nationwide cohort, this study aimed to determine the risk of suicide after the use of a 5α-reductase inhibitor, an antiandrogenic medication commonly used in the treatment of lower urinary tract symptoms.

Methods

A retrospective population-based cohort study was performed using the Korean National Health Insurance Service database. The study consisted of 51,466 men 60 years or older who underwent health examinations between 2005 and 2006. Individuals using a 5α-reductase inhibitor were compared with nonusers based on drug exposure between 2003 and 2006. Individuals using a 5α-reductase inhibitor were additionally divided into tertiles based on cumulative 5α-reductase inhibitor exposure. The incidence of completed suicide was documented during 7 years of follow-up, starting January 1, 2007.

Results

No significant risk of suicide was observed among 5α-reductase inhibitor users compared with 5α-reductase inhibitor nonusers (hazard ratio = 1.02, 95% confidence interval = 0.70–1.48). Cumulative 5α-reductase inhibitor exposure was also not associated with increased risk of suicide (p for trend = .543).

Conclusions

5α-Reductase inhibitor use was not associated with an elevated risk of suicide during a long-term follow-up period. A limitation of this study is that possible drug exposure after the index date was not accounted for. Although 5α-reductase inhibitor may increase the risk of depressive symptoms, the present data indicate that the drug is safe in terms of long-term suicide risk.
Right-Angled Traction Bronchiectasis in Differentiating Idiopathic Pulmonary Fibrosis Without Honeycombing From Idiopathic Nonspecific Interstitial Pneumonia
Authors: Kim Heekyung , Yoon Soon Ho , Lee Hyun-Ju , Song Seung Geun , Koh Jaemoon , Jeon Yoon Kyung , Chae Kum Ju , Jin Gong Yong , Jin Kwang Nam , Lee Ki Yeol , Goo Jin Mo
Published: February 2020

Objectives

The aim of this study was to conduct a radiopathologic evaluation of right-angled traction bronchiectasis to differentiate idiopathic pulmonary fibrosis (IPF) without honeycombing from idiopathic nonspecific interstitial pneumonia (NSIP).

Materials and Methods

The derivation cohort included 78 consecutive patients with idiopathic NSIP (n = 39) or IPF (n = 39) without honeycombing who underwent preoperative thin-section computed tomography scans at a single tertiary hospital. The validation cohort comprised 22 patients (14 IPF and 8 NSIP) from another institution. We assessed conventional computed tomography findings, right-angled traction bronchiectasis on minimum intensity projection (MinIP) images, and pathologic features associated with right-angled bronchiectasis. Right-angled traction bronchiectasis was defined as abrupt kinking of a single bronchus by over 90 degrees or an abrupt angle close to 180 degrees of branching bronchi in the background of fibrosis. In the validation cohort, we evaluated the proportion of correct IPF diagnoses and interobserver agreement of 4 radiologists before and after reviewing MinIP images.

Results

A probable usual interstitial pneumonia (UIP) pattern (odds ratio [OR], 6.948; 95% confidence interval [CI], 1.525–31.654; P = 0.012) and right-angled traction bronchiectasis (OR, 6.004; 95% CI, 1.980–18.209; P = 0.002) were independently associated with IPF. Patients with right-angled traction bronchiectasis were more likely to have extensive reticular opacity (OR, 1.149; 95% CI, 1.077–1.225; P < 0.001) and pathologically were more likely to have a broad extent of subpleural fibrosis (OR, 4.000; 95% CI, 1.457–10.987; P = 0.007) and relatively thick fibrosis (OR, 7.750; 95% CI, 2.504–23.991; P < 0.001). After reviewing MinIP images, the proportion of correct diagnoses increased from 40.9% to 54.5% to 50.0% to 77.3%. The mean kappa value for right-angled traction bronchiectasis was 0.489 ± 0.192.

Conclusions

Right-angled traction bronchiectasis pathologically reflected a subpleural predominance of fibrosis and partly supported the radiologic differentiation of IPF without honeycombing from idiopathic NSIP.
Acupuncture inhibits reinstatement of intravenous methamphetamine self-administration via gamma aminobutyric acid pathway
Authors: Kim Yo Han , Zhao Rong Jie , Lee Soo Min , Kim Mi Seon , Lim Sung Chul , Kim Jae Soo , Lee Hyun Jong , Yang Chae Ha , Kim Hee Young , Lee Yun Kyu , Lee Bong Hyo
Published: February 2020

Methamphetamine is one of the widely abused drugs. Nevertheless, there is little predominant therapy for the abuse. In the previous study, acupuncture had shown to attenuate methamphetamine self-administration behavior, and based on, the present study investigated whether acupuncture inhibits the reinstatement of methamphetamine self-administration. As well, a possible neuronal mechanism was investigated. Male Sprague–Dawley rats weighing 270–300 g were trained to intravenously self-administer methamphetamine (0.1 mg/kg) for 3 weeks. Following training, rats who administered stable amount of methamphetamine underwent extinction period of 1 week. Thereafter, priming injection was performed to induce reinstatement, and acupuncture was given immediately before priming. In the second experiment, the selective antagonists of GABAA and GABAB receptors were treated prior to acupuncture to investigate a neuronal mechanism of GABAergic pathway. Acupuncture treatment at HT7, but not at the control acupoint LI5, reduced the active lever responses on the reinstatement session, showing that HT7 suppressed craving for methamphetamine induced by reexposure to the drug during abstinence. And, the effects of acupuncture were blocked by the GABA receptors’ antagonists. In addition, HT7 did not influence saline self-administration, indicating that acupuncture effect was selective to the methamphetamine. Results of the present study show that acupuncture at HT7 suppresses reinstatement of methamphetamine self-administration behavior through the GABA receptor system without affecting the normal state. From the results, it may be suggested that acupuncture at HT7 can be a useful option in the treatment of methamphetamine addiction.
Targeting the anterior cingulate with bipolar and high-definition transcranial direct current stimulation
Authors: Kaur Navneet , Whitman Ethan T. , Moser Amelia D. , Hinojosa Cecilia A. , VanElzakker Michael B. , Camprodon Joan A. , Brunyé Tad T. , Shin Lisa M.
Published: February 2020

Research on the feasibility of using transcranial direct current stimulation to modulate the function of the anterior cingulate cortex is limited in part due to its anatomical depth. However, high-definition transcranial direct current stimulation may be better able to reach the anterior cingulate cortex and modulate its function and behavioral outputs. The purpose of this study was to assess the feasibility of using high-definition transcranial direct current stimulation, as compared to traditional bipolar transcranial direct current stimulation, to modulate behavioral measures of anterior cingulate cortex function. In a mixed design, 36 participants received either high-definition transcranial direct current stimulation or bipolar transcranial direct current stimulation, and experienced anodal, cathodal, and sham stimulation over the course of three visits. Two behavioral tasks were used to assess anterior cingulate cortex function before and after stimulation: the multi-source interference task and an emotional facial expression interference task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation groups did not differ in their performance (as measured via response times and error rates) on either task. High-definition transcranial direct current stimulation and bipolar transcranial direct current stimulation were similarly ineffective in modulating behavior related to the anterior cingulate cortex. Future research should explore other transcranial direct current stimulation montages including extracephalic montages (e.g. shoulder, neck) for targeted stimulation of the anterior cingulate cortex.
Climate and urbanization drive mosquito preference for humans
Authors: Rose Noah H. , Sylla Massamba , Badolo Athanase , Lutomiah Joel , Ayala Diego , Aribodor Ogechukwu B. , Ibe Nnenna , Akorli Jewelna , Otoo Sampson , Mutebi John-Paul , Kriete Alexis L. , Ewing Eliza G. , Sang Rosemary , Gloria-Soria Andrea , Powell Jeffrey R. , Baker Rachel E. , White Bradley J. , Crawford Jacob E. , McBride Carolyn S.
Published: February 2020

The majority of mosquito-borne illness is spread by a few mosquito species that have evolved to specialize in biting humans, yet the precise causes of this behavioral shift are poorly understood. We address this gap in the arboviral vectorAedes aegypti. We first characterize the behaviour of mosquitoes from 27 sites scattered across the species’ ancestral range in sub-Saharan Africa, revealing previously unrecognized diversity in female preference for humanversusanimal odor. We then use modelling to show that this diversity can be almost fully predicted by two ecological factors – dry season intensity and human population density. Finally we integrate this information with whole genome sequence data from 345 individual mosquitoes to identify a single underlying ancestry component linked to human preference, with genetic changes concentrated in a few key chromosomal regions. Our findings strongly suggest that human-biting in this important disease vector originally evolved as a by-product of breeding in human-stored water in areas where doing so provided the only means to survive the long, hot dry season. Our model also predicts that changes in human population density are likely to drive future mosquito evolution. Rapid urbanization may drive a shift to human-biting in many cities across Africa by 2050.
Modeling reveals human-rodent differences in h-current kinetics influencing resonance in cortical layer 5 neurons
Authors: Rich Scott , Chameh Homeira Moradi , Sekulic Vladislav , Valiante Taufik A. , Skinner Frances K.
Published: February 2020

While our understanding of human neurons is often inferred from rodent data, inter-species differences between neurons can be captured by building cellular models specifically from human data. This includes understanding differences at the level of ion channels and their implications for human brain function. Thus, we here present a full spiking, biophysically-detailed multi-compartment model of a human layer 5 (L5) cortical pyramidal cell. Model development was primarily based on morphological and electrophysiological data from the same human L5 neuron, avoiding confounds of experimental variability. Focus was placed on describing the behavior of the hyperpolarization-activated cation (h-) channel, given increasing interest in this channel due to its role in pacemaking and differentiating cell types. We ensured that the model exhibited post-inhibitory rebound (PIR) spiking considering its relationship with the h-current, along with other general spiking characteristics. The model was validated against data not used in its development, which highlighted distinctly slower kinetics of the human h-current relative to the rodent setting. We linked the lack of subthreshold resonance observed in human L5 neurons to these human-specific h-current kinetics. This work shows that it is possible and necessary to build human-specific biophysical neuron models in order to understand human brain dynamics.
A mathematical model of ctDNA shedding predicts tumor detection size
Authors: Avanzini Stefano , Kurtz David M. , Chabon Jacob J. , Moding Everett J. , Hori Sharon Seiko , Gambhir Sanjiv Sam , Alizadeh Ash A. , Diehn Maximilian , Reiter Johannes G.
Published: February 2020

Early cancer detection aims to find tumors before they progress to an incurable stage. We developed a stochastic mathematical model of tumor evolution and circulating tumor DNA (ctDNA) shedding to determine the potential and the limitations of cancer early detection tests. We inferred normalized ctDNA shedding rates from 176 early stage lung cancer subjects and calculated that a 15 mL blood sample contains on average 1.7 genome equivalents of ctDNA for lung tumors with a volume of 1 cm3. For annual screening, the model predicts median detection sizes between 3.8 and 6.6 cm3corresponding to lead times between 310 and 450 days compared to current lung tumor sizes at diagnosis. For monthly cancer relapse testing based on 20 a priori known mutations, the model predicts a median detection size of 0.26 cm3corresponding to a lead time of 150 days. This mechanistic framework can help to optimize early cancer detection approaches.
Widespread selection against deleterious mutations in theDrosophilagenome
Authors: Khromov Pavel , Morozov Alexandre V.
Published: February 2020

We have developed a computational approach to simultaneous genome-wide inference of key population genetics parameters: selection strengths, mutation rates rescaled by the effective population size and the fraction of viable genotypes, solely from an alignment of genomic sequences sampled from the same population. Our approach is based on a generalization of the Ewens sampling formula, used to compute steady-state probabilities of allelic counts in a neutrally evolving population, to populations subjected to selective constraints. Patterns of polymorphisms observed in alignments of genomic sequences are used as input to Approximate Bayesian Computation, which employs the generalized Ewens sampling formula to infer the distributions of population genetics parameters. After carrying out extensive validation of our approach on synthetic data, we have applied it to the evolution of theDrosophila melanogastergenome, where an alignment of 197 genomic sequences is available for a single ancestral-range population from Zambia, Africa. We have divided theDrosophilagenome into 100-bp windows and assumed that sequences in each window can exist in either low- or high-fitness state. Thus, the steady-state population in our model is subject to a constant influx of deleterious mutations, which shape the observed frequencies of allelic counts in each window. Our approach, which focuses on deleterious mutations and accounts for intra-window linkage and epistasis, provides an alternative description of background selection. We find that most of theDrosophilagenome evolves under selective constraints imposed by deleterious mutations. These constraints are not confined to known functional regions of the genome such as coding sequences and may reflect global biological processes such as the necessity to maintain chromatin structure. Furthermore, we find that inference of mutation rates in the presence of selection leads to mutation rate estimates that are several-fold higher than neutral estimates widely used in the literature. Our computational pipeline can be used in any organism for which a sample of genomic sequences from the same population is available.
Predicting molecular subtypes of breast cancer using pathological images by deep convolutional neural network from public dataset
Authors: Phan Nam Nhut , Huang Chi-Cheng , Chuang Eric Y
Published: February 2020

Breast cancer is a heterogeneously complex disease. A number of molecular subtypes with distinct biological features lead to different treatment responses and clinical outcomes. Traditionally, breast cancer is classified into subtypes based on gene expression profiles; these subtypes include luminal A, luminal B, basal like, HER2-enriched, and normal-like breast cancer. This molecular taxonomy, however, could only be appraised through transcriptome analyses. Our study applies deep convolutional neural networks and transfer learning from three pre-trained models, namely ResNet50, InceptionV3 and VGG16, for classifying molecular subtypes of breast cancer using TCGA-BRCA dataset. We used 20 whole slide pathological images for each breast cancer subtype. The results showed that our scale training reached about 78% of accuracy for validation. This outcomes suggested that classification of molecular subtypes of breast cancer by pathological images are feasible and could provide reliable results
The Tumor Profiler Study: Integrated, multi-omic, functional tumor profiling for clinical decision support
Authors: Irmisch Anja , Bonilla Ximena , Chevrier Stéphane , Lehmann Kjong-Van , Singer Franziska , Toussaint Nora C , Esposito Cinzia , Mena Julien , Milani Emanuela S , Casanova Ruben , Stekhoven Daniel J , Wegmann Rebekka , Jacob Francis , Sobottka Bettina , Goetze Sandra , Kuipers Jack , del Castillo Jacobo Sarabia , Prummer Michael , Tuncel Mustafa , Menzel Ulrike , Jacobs Andrea , Engler Stefanie , Sivapatham Sujana , Frei Anja , Gut Gabriele , Ficek Joanna , Dummer Reinhard ,   Tumor Profiler Consortium, Aebersold Rudolf , Bacac Marina , Beerenwinkel Niko , Beisel Christian , Bodenmiller Bernd , Koelzer Viktor H , Moch Holger , Pelkmans Lucas , Snijder Berend , Tolnay Markus , Wollscheid Bernd , Rätsch Gunnar , Levesque Mitchell
Published: February 2020

Recent technological advances allow profiling of tumor samples to an unparalleled level with respect to molecular and spatial composition as well as treatment response. We describe a prospective, observational clinical study performed within the Tumor Profiler (TuPro) Consortium that aims to show the extent to which such comprehensive information leads to advanced mechanistic insights of a patient’s tumor, enables prognostic and predictive biomarker discovery, and has the potential to support clinical decision making. For this study of melanoma, ovarian carcinoma, and acute myeloid leukemia tumors, in addition to the emerging standard diagnostic approaches of targeted NGS panel sequencing and digital pathology, we perform extensive characterization using the following exploratory technologies: single-cell genomics and transcriptomics, proteotyping, CyTOF, imaging CyTOF, pharmacoscopy, and 4i drug response profiling (4i DRP). In this work, we outline the aims of the TuPro study and present preliminary results on the feasibility of using these technologies in clinical practice showcasing the power of an integrative multi-modal and functional approach for understanding a tumor’s underlying biology and for clinical decision support.
Erosion of representativeness in a cohort study
Authors: Christodoulou M.D. , Brettschneider J.A. , Steinsaltz D.
Published: February 2020

Background

The National Child and Development Study (1958 British Birth Cohort) follows the lives of over 17 000 people born in a single week in England, Scotland, and Wales. Since the initial recruitment there have been nine sweeps to gather subsequent life-course data, and a Biomedical Sweep (Age 44) – between Sweeps 6 (Age 42) and 7 (Age 46) – that has found widespread application in genetic studies. Due to its non-selective recruitment, the survey is frequently used as a representative proxy for the British population in demographic, epidemiological, and medical studies. We examine the effect of attrition on representativeness of female fertility and education length.

Methods

We compare numbers and timings of fertility-related events of female cohort members with national estimates. Spline approximation was used to link records with different aggregation intervals. Participants present in the Biomedical Sweep (Age 44) were compared to those who were not.

Results

We established that both timings and counts of maternities and terminations in the cohort diverge from the patterns of their contemporaries. For women who participated in the Biomedical Sweep (Age 44), we noted positive correlations of study continuation with years spent in full time education, and with age at first birth. We determined that women who did not participate in the Biomedical Sweep (Age 44) reported different fertility patterns from those who did.

Conclusions

It is possible to use National Statistics to quantify various forms of selection bias that inevitably creep into even the most meticulously sampled longitudinal study, and the misreporting that affects particular questions. While the 1958 Birth Cohort has reasonably been described as “broadly representative” of the British population, such a characterisation becomes questionable when the data are to be applied to questions about female fertility.

KEY MESSAGES

Fertility patterns of women reported in later sweeps of the 1958 British Birth Cohort diverge from those of their contemporaries as estimated from national statistics using spline approximation. Both maternities and terminations are underreported.

Female participants who dropped out earlier follow national maternity trends more closely than those who participated in the study longer, but they still report slightly fewer maternities than national statistics suggest.

Female participants who persisted through later sweeps experienced first births later and left education at a later age than those who dropped out earlier.

Although the 1958 British Birth Cohort has been judged as representative of the British population for some research questions, the cohort population presents increasingly biased fertility patterns in female participants over time. Studies related to fertility using data from this cohort may require adjustment.
Machine Boss: Rapid Prototyping of Bioinformatic Automata
Authors: Silvestre-Ryan J. , Wang Y. , Sharma M. , Lin S. , Shen Y. , Dider S. , Holmes I.
Published: February 2020

Motivation

Many C++ libraries for using Hidden Markov Models in bioinformatics focus on inference tasks, such as likelihood calculation, parameter-fitting, and alignment. However, construction of the state machines can be a laborious task, automation of which would be time-saving and less error-prone.

Results

We present Machine Boss, a software tool implementing not just inference and parameter-fitting algorithms, but also a set of operations for manipulating and combining automata. The aim is to make prototyping of bioinformatics HMMs as quick and easy as the construction of regular expressions, with one-line “recipes” for many common applications. We report data from several illustrative examples involving protein-to-DNA alignment, DNA data storage, and nanopore sequence analysis.

Availability and Implementation

Machine Boss is released under the BSD-3 open source license and is available fromhttp://machineboss.org/.

Contact

Ian Holmes,ihh@berkeley.edu
Validating the potential of double-stranded RNA targeting Colorado potato beetlemeshgene in laboratory and field trials
Authors: Petek Marko , Coll Anna , Ferenc Rok , Razinger Jaka , Gruden Kristina
Published: February 2020

Colorado potato beetle (CPB) is an agricultural pest of solanaceous crops, notorious for its rapid resistance development to chemical pesticides. Foliar spraying of dsRNA formulations is a promising innovative technology providing highly specific and environmentally acceptable option for CPB management.

We designed dsRNA to silence CPBmeshgene (dsMESH) and performed laboratory feeding trials to assess impacts on beetle survival and development. We compared the effectiveness ofin-vivoandin-vitroproduced dsRNA in a series of laboratory experiments. We additionally performed a field trial in which the efficacy of dsRNA sprayed onto potato foliage was compared to a spinosad-based insecticide.

We showed that dsMESH ingestion consistently and significantly impaired larval growth and decreased larval survival in laboratory feeding experiments.In-vivoproduced dsRNA performed similarly asin-vitrosynthesised dsRNA in laboratory settings. In the field trial, dsMESH was as effective in controlling CPB larvae as a commercial spinosad insecticide, its activity was however slower. We discuss limitations and benefits of a potential dsMESH-based CPB management strategy and list some important RNAi based CPB research topics, which will have to be addressed in future.
Defective heart chamber growth and myofibrillogenesis after knockout ofadprhl1gene function by targeted disruption of the ancestral catalytic active site
Authors: Smith Stuart J. , Towers Norma , Demetriou Kim , Mohun Timothy J.
Published: February 2020

ADP-ribosylhydrolase-like 1 (Adprhl1) is a pseudoenzyme expressed in the developing heart myocardium of all vertebrates. In the amphibianXenopus laevis, knockdown of the two cardiac Adprhl1 protein species (40 and 23 kDa) causes failure of chamber outgrowth but this has only been demonstrated using antisense morpholinos that interfere with RNA-splicing. Transgenic production of 40 kDa Adprhl1 provides only part rescue of these defects. CRISPR/Cas9 technology now enables targeted mutation of theadprhl1gene in G0-generation embryos with routine cleavage of all alleles. Testing multiple gRNAs distributed across the locus reveals exonic locations that encode critical amino acids for Adprhl1 function. The gRNA recording the highest frequency of a specific ventricle outgrowth phenotype directs Cas9 cleavage of an exon 6 sequence, where microhomology mediated end-joining biases subsequent DNA repairs towards three small in-frame deletions. Mutant alleles encode discrete loss of 1, 3 or 4 amino acids from a di-arginine (Arg271-Arg272) containing peptide loop at the centre of the ancestral ADP-ribosylhydrolase site. Thus despite lacking catalytic activity, it is the modified (adenosine-ribose) substrate binding cleft of Adprhl1 that fulfils an essential role during heart formation. Mutation results in striking loss of myofibril assembly in ventricle cardiomyocytes. The defects suggest Adprhl1 participation from the earliest stage of cardiac myofibrillogenesis and are consistent with previous MO results and Adprhl1 protein localization to actin filament Z-disc boundaries. A single nucleotide change to the gRNA sequence renders it inactive. Mice lackingAdprhl1exons 3-4 are normal but production of the smaller ADPRHL1 species is unaffected, providing further evidence that cardiac activity is concentrated at the C-terminal protein portion.

Highlights

Comparison ofadprhl1morpholinos. Knockdown of the twoXenopuscardiac Adprhl1 protein species (40 and 23 kDa) causes failure of ventricle outgrowth.

CRISPR/Cas9 targeted gene mutation ofadprhl1with multiple gRNAs reveals exonic locations that encode critical amino acids for Adprhl1 function.

Repair of DSBs at exon 6 yields small in-frame deletions that cause specific ventricle myofibril assembly defects.

The deletions disturb a conserved di-arginine containing peptide loop at the centre of the ancestral substrate binding cleft/ADP-ribosylhydrolase site of this pseudoenzyme.

Mice lackingAdprhl1exons 3-4 are normal but production of the smaller ADPRHL1 species is unaffected, providing further evidence that cardiac activity is concentrated at the C-terminal protein portion.
Prior expectations evoke stimulus templates in the deep layers of V1
Authors: Aitken Fraser , Menelaou Georgios , Warrington Oliver , Koolschijn Renée S. , Corbin Nadège , Callaghan Martina F. , Kok Peter
Published: February 2020

The way we perceive the world is strongly influenced by our expectations. In line with this, much recent research has revealed that prior expectations strongly modulate sensory processing. However, the neural circuitry through which the brain integrates external sensory inputs with internal expectation signals remains unknown. In order to understand the computational architecture of the cortex, we need to investigate the way these signals flow through the cortical layers. This is crucial because the different cortical layers have distinct intra- and interregional connectivity patterns, and therefore determining which layers are involved in a cortical computation can inform us on the sources and targets of these signals. Here, we used ultra-high field (7T) functional magnetic resonance imaging (fMRI) to reveal that prior expectations evoke stimulus templates selectively in the deep layers of the primary visual cortex. These results shed light on the neural circuit underlying perceptual inference.