bluuebunny/crossref_metadata_2025 huggingface dataset:
International Law for Transboundary Aquifers: A Challenge for Our Times
Authors: Eckstein Gabriel
Published: May 2021

Quarrels between states sharing a transboundary aquifer (TBA) have been relatively minor in comparison with the more boisterous disputes seen in many of the world's shared river basins. Yet, transboundary groundwater can easily serve as the basis for cross-border disagreements. Twice as many TBAs and shared groundwater bodies have been identified globally as compared to transboundary rivers and lakes, and the volume of accessible groundwater exceeds all surface waters by a factor of one hundred. Yet, the number of treaties in force for TBAs is miniscule in comparison with those for transboundary rivers and lakes. Moreover, dozens of nations exploit groundwater from a TBA, often unilaterally and without knowing the cross-border implications, or even that the aquifer is transboundary. The lack of prioritization of groundwater in international practice and law, coupled with the reality that groundwater is “out of sight,” and thereby “out of mind,” has relegated shared aquifers as the neglected stepchildren of international water law. But, with many of the world's nations experiencing growing water scarcity and stress, this situation undoubtedly will change. This essay highlights the growing pains of international groundwater law and the challenges for its identification and articulation. Specific hydrogeologic characteristics of various TBAs are presented and, where relevant, placed in the context of water scarcity and security and recognized international legal norms.
Prior Notification and Water Rights
Authors: Tignino Mara
Published: May 2021

International practice, including international instruments and case law, confirms that states generally accept that they have a duty to provide prior notification of planned measures that may have a significant adverse effect upon co-riparians. The principle of “prior notification” is framed differently in various instruments, and it can broadly include the duty to “notify” and “consult” on planned measures. Prior notification helps to prevent and mitigate disputes, as underlined by the ICJ. Notification and consultation create the conditions for cooperation among riparian states and for ensuring the protection of international watercourses. On the contrary, the lack of notification and consultation may aggravate disputes as in the case of the Great Renaissance Dam along the Nile River. The UN Convention on the Law of the Non-Navigational Uses of International Watercourses (Watercourses Convention) provides a detailed procedural framework on prior notification and consultation. This essay outlines the established characteristics of the prior notification and consultation duty, then argues that the duty should be viewed not only as an inter-state obligation but also as including the obligation to inform and consult local communities.
Whole of (coalition) government: Comparing Swedish and German experiences in Afghanistan
Authors: Dafinova Maya
Published: May 2021

Whole-of-government (WOG) approaches have emerged as a blueprint for contemporary peace and state-building operations. Countries contributing civilian and military personnel to multinational interventions are persistently urged to improve coherence and enhance coordination between the ministries that form part of the national contingent. Despite a heated debate about what WOG should look like and how to achieve it, the causal mechanisms of WOG variance remains under-theorised. Based on 47 in-depth, semi-structured interviews, this study compares Swedish and German WOG approaches in the context of the International Security Assistance Force (ISAF). I argue that coalition bargaining drove the fluctuation in the Swedish and German WOG models. Strategic culture was an antecedent condition. In both cases, COIN and the war on terror clashed with foundational elements of the Swedish and German strategic cultures, paving the way for a non-debate on WOG on the political arena. Finally, bureaucratic politics was an intervening condition that obstructed or enabled coherence, depending on the ambition of the incumbent coalition government to progress WOG. Overall, the results suggest that coalitions face limitations in implementing a WOG framework when the nature of the military engagement is highly disputed in national parliaments.
Standardized aseptic dressing change procedure: Optimizations and adherence in a prospective pre- and postintervention cohort study
Authors: Neuwirth Meike M. , Herbrandt Swetlana , Mattner Frauke , Otchwemah Robin
Published: May 2021

Background:

The “HygArzt” project investigated the effectiveness of hygiene measures introduced by an infection prevention link physician (PLP).

Objective:

To investigate whether the introduction of a standardized aseptic dressing change concept (ADCC) by a PLP can increase hand hygiene adherence and adherence to specific process steps during an aseptic dressing change (ADC) in a trauma surgery and orthopedic department.

Methods:

We defined 4 required hand disinfection indications: (1) before the preparation of ADC equipment, (2) immediately before the ADC, (3) before the clean phase, and (4) after the ADC. A process analysis of the preintervention phase (331 ADCs) was used to develop a standardized ADCC. The ADCC was introduced and iteratively adopted during the intervention phase. The effect was evaluated during the postintervention phase (374 ADCs).

Results:

Hand hygiene adherence was significantly increased by the introduction of the ADCC for all indications: (1) before the preparation of the ADC equipment (from 34% before to 85% after, P <.001), (2) immediately before an ADC (from 32% before to 85% after; P < .001), (3) before the clean phase (from 42% before to 96% after; P < .001), and (4) after an ADC (from 74% before to 99% after; P < .001). Overall hand hygiene adherence was analyzed before the indications for an ADC (from 9.6% before to 74% after; P < .001). The same strategy was applied to the following process parameters: use of a clean work surface, clean withdrawal of equipment from the dressing trolley, and appropriate waste disposal.

Conclusions:

A PLP sufficiently implemented a standardized concept for aseptic dressing change during an iterative improvement process, which resulted in a significant improvement in hand hygiene and adherence to other specific ADCC process steps.
Love in the time of Covid-19: a case-study of the complex laws governing weddings
Authors: Probert Rebecca , Pywell Stephanie
Published: May 2021

During 2020, weddings were profoundly affected by the Covid-19 pandemic. During periods of lockdown few weddings could take place, and even afterwards restrictions on how they could be celebrated remained. To investigate the impact of such restrictions, we carried out a survey of those whose plans to marry in England and Wales had been affected by Covid-19. The 1,449 responses we received illustrated that the ease and speed with which couples had been able to marry, and sometimes whether they had been able to marry at all, had depended not merely on the national restrictions in place but on their chosen route into marriage. This highlights the complexity and antiquity of marriage law and reinforces the need for reform. The restrictions on weddings taking place also revealed the extent to which couples valued getting married as opposed to having a wedding. Understanding both the social and the legal dimension of weddings is important in informing recommendations as to how the law should be changed in the future, not merely to deal with similar crises but also to ensure that the general law is fit for purpose in the twenty-first century.
Cultural History and Modern Science
Authors: Long Max
Published: May 2021

The term ‘cultural history of science’, as others have observed, is clumsy and imperfect. Cultural history is itself riddled with ambiguities which the addition of ‘science’ is unlikely to clarify. However, the term loosely describes a genre of historical writing which has become a staple of cross-disciplinary research: books which examine science's wider cultural ‘impacts’ and ‘contexts’. The heterogeneity of this field is so great, however, that an examination of methodology is called for.
Negative Utility Monsters
Authors: Chappell Richard Yetter
Published: May 2021

Many consider Nozick's “utility monster” – a being more efficient than ordinary people at converting resources into wellbeing, with no upper limit – to constitute a damning counterexample to utilitarianism. But our intuitions may be reversed by considering a variation in which the utility monster starts from a baseline status of massive suffering. This suggests a rethinking of the force of the original objection.
Surgical versus transcatheter palliation for insufficient pulmonary blood supply in infants with cyanotic CHD
Authors: Ho Andrew B. , Perry Thomas , Hribernik Ines , Thomson John D. , Bentham James R.
Published: May 2021

Infants with complex cyanotic CHD can become symptomatic from insufficient pulmonary blood supply following either ductal closure or due to outflow tract obstruction. Blalock–Taussig shunt mortality remains significant and recent studies have highlighted the advantages of using transcatheter alternatives. We present here our experience in changing our primary choice of palliation from the Blalock–Taussig shunt to transcatheter palliation with either a ductal stent or, if antegrade flow is present, a right ventricular outflow tract stent.

This is a retrospective, single-unit cohort study. Eighty-seven infants underwent palliation for insufficient pulmonary blood flow at under 3 months of age between 2012 and 2019. On an intention-to-treat basis, 29 underwent insertion of a Blalock–Taussig shunt, 36 duct stents, and 22 right ventricular outflow tract stents at median ages of 15, 9, and 32 days, respectively, and median weights of 3.3, 3.1, and 3.1 kg, respectively. No primary Blalock–Taussig shunts have been performed in our institution since 2017.

At 30-days there had been one death in each group (univariable p = 0.93) and deaths prior to repair totalled three in the shunt group, four in the ductal stent group, and two in the right ventricular outflow tract stent group (univariable p = 0.93). Reintervention on the pulmonary circuit prior to next stage of surgery was more frequent in those undergoing transcatheter intervention, reaching statistical significance by logrank (p = 0.012).

In conclusion, within this work we provide further evidence of the safety and efficacy of transition from a primary surgical to primary transcatheter palliation pathway in infants with insufficient pulmonary blood supply.
Exploring the Semantic Structure of WMS-IV Verbal Paired Associates using the Hub-and-Spoke Model
Authors: Furey Rachel T. , Bowden Stephen C. , Simpson Leonie C. , Meade Catherine E. , Davis Brooke M. , D’Souza Wendyl J.
Published: May 2021

Objectives:

This study aimed to identify a well-fitting and theoretically justified item-level latent factor structure for the Wechsler Memory Scales (WMS)-IV verbal paired associates (VerbalPA) subtest to facilitate the ease and accuracy of score interpretations for patients with lateralized temporal lobe epilepsy (TLE).

Methods:

Archival data were used from 250 heterogeneous neurosciences patients who were administered the WMS-IV as part of a standard neuropsychological assessment. Three theoretically motivated models for the latent structure of VerbalPA were tested using confirmatory factor analysis. The first model, based on cognitive principles of semantic processing from hub-and-spoke theory, tested whether performance is related to specific semantic features of target words. The second, motivated by the Cattell–Horn–Carroll (CHC) model of cognitive abilities, investigated whether the associative properties of items influence performance. A third, Hybrid model tested whether performance is related to both semantic and associative properties of items. The best-fitting model was tested for diagnostic group effects contrasting the heterogeneous neuroscience patients with subsets of left and right TLE (n = 51, n = 26, respectively) patients.

Results:

The Hybrid model was found to have the best fit. Patients with left TLE scored significantly less well than the heterogeneous neurosciences sample on selected semantic factor scores, although the effect size was small.

Conclusions:

Future editions of the WMS may consider implementing a semantic scoring structure for the VerbalPA to facilitate test score interpretation. Additionally, these results suggest that principles of hub-and-spoke theory may be integrated into CHC cognitive ability taxonomy.
Divine Sovereignty and Clerical Authority in Early Shi‘i Islamism: Bāqir al-Ṣadr (1935–80) and Taqī al-Mudarrisī (b. 1945) on the Islamic State
Authors: SCHARBRODT OLIVER
Published: May 2021

Divine sovereignty (ḥākimiyya)—as conceived by Abū al-A‘lā Mawdūdī (1903–79) and popularised by Sayyid Quṭb (1906–66) - has been a central component of Islamist thought. This article investigates the reception of the concept within Shi‘i Islam. As case studies, the article choses two prominent actors in the formative period of Shi‘i Islamism in Iraq: Muḥammad Bāqir al-Ṣadr (1935–80) and Muḥammad Taqī al-Mudarrisī (b. 1945). By discussing their reflections on the nature of an Islamic state, the article pursues three objectives: first, it overcomes a trend in academic scholarship that disregards Sunni influences on the development of Shi‘i Islamism. Second, the article highlights the role that the Iraqi Shi‘i intellectual milieu played in incorporating key Islamist concepts into Shi‘i political thought. Finally, the article demonstrates the different receptions of ḥākimiyya. Bāqir al-Ṣadr uses the ideological repertoire of Islamism to explore in pragmatic terms the parameters that define the state as Islamically legitimate. In contrast, Taqī al-Mudarrisī uses ḥākimiyya to redefine the sovereignty of the state in Islamic terms. He operationalises the concept in a Shi‘i context by arguing that the state must be led by a just jurisconsult (al-faqīh al-‘ādil) who becomes the sole agent of divine sovereignty in the state.
Should We Worry About Silicone Chip Technology De-Skilling Us?
Authors: Fricker Elizabeth
Published: May 2021

It is argued that many means-end skills are mere drudgery, and there is no case from well-being to regret that the advance of technology has replaced them with machines. But a case is made that for humans possessing some skills is important for well-being, and that certain core skills are important for it. It is argued that these include navigational skills. While the march of technology has tended to promote human well-being, there is now some cause for concern that silicone chip technology is de-skilling us to an extent that impacts negatively on well-being.
Validation of MEDFICTS Dietary Assessment Questionnaire in Turkish Population
Authors: Göktaş Zeynep , Dikmen Derya , Rakıcıoğlu Neslişah
Published: May 2021

Objective:

The purpose of this study was to assess the validity of MEDFICTS (Meats, Eggs, Dairy, Fried foods, fat In baked goods, Convenience foods, fats added at the Table, Snacks) questionnaire in Turkish population.

Design:

MEDFICTS questionnaire is a brief dietary assessment tool developed as part of the National Cholesterol Education Program Adult Treatment Panel guidelines, and it measures the adherence to Step 1 and Step 2 diets that are recommended for the prevention and treatment of CVD. MEDFICTS questionnaire was administered with 3-d food record to compare overall dietary fat intake.

Setting:

This study was conducted at the Hacettepe University (Ankara, Turkey) in 2017.

Participants:

Subjects were university students, recruited from several departments of Hacettepe University by trained dietitians. A total of 442 adults (249 females and 194 males) between the ages of 18 and 31 years participated in the study. Students with CVD were excluded.

Results:

Total fat intake ratio was higher than the recommended level for both males and females (39·4 % and 39·9 %, respectively). Mean MEDCISTS score was 66·3 ± 27·24 points. Total energy, total fat, SFA and cholesterol intakes from 3-d food records within the different MEDFICTS diet groups significantly differed (P < 0·001 for all). Receiver operating characteristics curve analysis demonstrated that a cut-off point of 60 showed 80 % sensitivity and 65 % specificity.

Conclusions:

Our data indicate that the MEDFICTS questionnaire is moderately accurate; however, sensitivity analysis did not demonstrate the recommended 40 points as an optimal cut-off point for Turkish population.
Nexus of self-organization: the expansion of collective responsibility networks among boatmen in nineteenth-century Chongqing
Authors: Pan Yiying
Published: May 2021

This article investigates the collective responsibility organizations among boatmen in nineteenth-century Chongqing, when the city became one of the most important metropolises on the southwest Qing frontier. It also introduces two successive turning points in self-organization that were associated with two different classes of boatmen – skippers and sailors. First, in 1803, skippers gained the authority to institutionalize their organizations through their negotiations with the local state regarding official services and service fees. Second, when similar service and fiscal tensions emerged between skippers and sailors in the mid-nineteenth century, the skippers facilitated and supervised the institutionalization of collective responsibility organizations that were run by the sailors themselves. By contextualizing this expansion of collective responsibility organizations within the multilayered interactions between skippers and sailors, this article proposes that the perspective of interclass networks is crucial for deepening the study of state−society interactions, the capital−labor relationship, as well as the tension between imperial integration and regional diversity in early modern China.
Double emulsion-pretreated microwell culture for the in vitro production of multicellular spheroids and their in situ analysis
Authors: Qu Fuyang , Zhao Shirui , Cheng Guangyao , Rahman Habibur , Xiao Qinru , Chan Renee Wan Yi , Ho Yi-Ping
Published: May 2021

Multicellular spheroids have served as a promising preclinical model for drug efficacy testing and disease modeling. Many microfluidic technologies, including those based on water–oil–water double emulsions, have been introduced for the production of spheroids. However, sustained culture and the in situ characterization of the generated spheroids are currently unavailable for the double emulsion-based spheroid model. This study presents a streamlined workflow, termed the double emulsion-pretreated microwell culture (DEPMiC), incorporating the features of (1) effective initiation of uniform-sized multicellular spheroids by the pretreatment of double emulsions produced by microfluidics without the requirement of biomaterial scaffolds; (2) sustained maintenance and culture of the produced spheroids with facile removal of the oil confinement; and (3) in situ characterization of individual spheroids localized in microwells by a built-in analytical station. Characterized by microscopic observations and Raman spectroscopy, the DEPMiC cultivated spheroids accumulated elevated lipid ordering on the apical membrane, similar to that observed in their Matrigel counterparts. Made possible by the proposed technological advancement, this study subsequently examined the drug responses of these in vitro-generated multicellular spheroids. The developed DEPMiC platform is expected to generate health benefits in personalized cancer treatment by offering a pre-animal tool to dissect heterogeneity from individual tumor spheroids.
PTSD is associated with accelerated transcriptional aging in World Trade Center responders
Authors: Kuan Pei-Fen , Ren Xu , Clouston Sean , Yang Xiaohua , Jonas Katherine , Kotov Roman , Bromet Evelyn , Luft Benjamin J.
Published: May 2021

Posttraumatic stress disorder (PTSD) is associated with shortened lifespan and healthspan, which suggests accelerated aging. Emerging evidence suggests that methylation age may be accelerated in PTSD. It is important to examine whether transcriptional age is also accelerated because transcriptome is highly dynamic, associated with age-related outcomes, and may offer greater insight into the premature aging in PTSD. This study is the first reported investigation of the relationship between transcriptional age and PTSD. Using RNA-Seq data from our previous study on 324 World Trade Center responders (201 never had PTSD, 81 with current PTSD, and 42 with past PTSD), as well as a transcriptional age calculator (RNAAgeCalc) recently developed by our group, we found that responders with current PTSD, compared with responders without a PTSD diagnosis, showed accelerated transcriptional aging (p = 0.0077) after adjustment for chronological age and race. We compared our results to the epigenetic aging results computed from several epigenetic clock calculators on matching DNA methylation data. GrimAge methylation age acceleration was also associated with PTSD diagnosis (p = 0.0097), and the results remained significant after adjustment for the proportions of immune cell types. PhenoAge, Hannum, and Horvath methylation age acceleration were not reliably related to PTSD. Both epigenetic and transcriptional aging may provide biological insights into the mechanisms underpinning aging in PTSD.
Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats
Authors: de Oliveira Amanda R. , Reimer Adriano E. , Simandl Gregory J. , Nagrale Sumedh S. , Widge Alik S.
Published: May 2021

The orbitofrontal cortex–ventromedial striatum (OFC–VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. Male Long-Evans rats implanted with optical fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC–VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after, and 1 h after each stimulation, 1 and 2 weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC–VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional set-shifting. OFC–VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes in the OFC–VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.
Phantom rivers filter birds and bats by acoustic niche
Authors: Gomes D. G. E. , Toth C. A. , Cole H. J. , Francis C. D. , Barber J. R.
Published: May 2021

Natural sensory environments, despite strong potential for structuring systems, have been neglected in ecological theory. Here, we test the hypothesis that intense natural acoustic environments shape animal distributions and behavior by broadcasting whitewater river noise in montane riparian zones for two summers. Additionally, we use spectrally-altered river noise to explicitly test the effects of masking as a mechanism driving patterns. Using data from abundance and activity surveys across 60 locations, over two full breeding seasons, we find that both birds and bats avoid areas with high sound levels, while birds avoid frequencies that overlap with birdsong, and bats avoid higher frequencies more generally. We place 720 clay caterpillars in willows, and find that intense sound levels decrease foraging behavior in birds. For bats, we deploy foraging tests across 144 nights, consisting of robotic insect-wing mimics, and speakers broadcasting bat prey sounds, and find that bats appear to switch hunting strategies from passive listening to aerial hawking as sound levels increase. Natural acoustic environments are an underappreciated niche axis, a conclusion that serves to escalate the urgency of mitigating human-created noise.
The 79°N Glacier cavity modulates subglacial iron export to the NE Greenland Shelf
Authors: Krisch Stephan , Hopwood Mark James , Schaffer Janin , Al-Hashem Ali , Höfer Juan , Rutgers van der Loeff Michiel M. , Conway Tim M. , Summers Brent A. , Lodeiro Pablo , Ardiningsih Indah , Steffens Tim , Achterberg Eric Pieter
Published: May 2021

Approximately half of the freshwater discharged from the Greenland and Antarctic Ice Sheets enters the ocean subsurface as a result of basal ice melt, or runoff draining via the grounding line of a deep ice shelf or marine-terminating glacier. Around Antarctica and parts of northern Greenland, this freshwater then experiences prolonged residence times in large cavities beneath floating ice tongues. Due to the inaccessibility of these cavities, it is unclear how they moderate the freshwater associated supply of nutrients such as iron (Fe) to the ocean. Here, we show that subglacial dissolved Fe export from Nioghalvfjerdsbrae (the ‘79°N Glacier’) is decoupled from particulate inputs including freshwater Fe supply, likely due to the prolonged ~162-day residence time of Atlantic water beneath Greenland’s largest floating ice-tongue. Our findings indicate that the overturning rate and particle-dissolved phase exchanges in ice cavities exert a dominant control on subglacial nutrient supply to shelf regions.
Microsecond fingerprint stimulated Raman spectroscopic imaging by ultrafast tuning and spatial-spectral learning
Authors: Lin Haonan , Lee Hyeon Jeong , Tague Nathan , Lugagne Jean-Baptiste , Zong Cheng , Deng Fengyuan , Shin Jonghyeon , Tian Lei , Wong Wilson , Dunlop Mary J. , Cheng Ji-Xin
Published: May 2021

Label-free vibrational imaging by stimulated Raman scattering (SRS) provides unprecedented insight into real-time chemical distributions. Specifically, SRS in the fingerprint region (400–1800 cm−1) can resolve multiple chemicals in a complex bio-environment. However, due to the intrinsic weak Raman cross-sections and the lack of ultrafast spectral acquisition schemes with high spectral fidelity, SRS in the fingerprint region is not viable for studying living cells or large-scale tissue samples. Here, we report a fingerprint spectroscopic SRS platform that acquires a distortion-free SRS spectrum at 10 cm−1spectral resolution within 20 µs using a polygon scanner. Meanwhile, we significantly improve the signal-to-noise ratio by employing a spatial-spectral residual learning network, reaching a level comparable to that with 100 times integration. Collectively, our system enables high-speed vibrational spectroscopic imaging of multiple biomolecules in samples ranging from a single live microbe to a tissue slice.
3D printable diffractive optical elements by liquid immersion
Authors: Orange-Kedem Reut , Nehme Elias , Weiss Lucien E. , Ferdman Boris , Alalouf Onit , Opatovski Nadav , Shechtman Yoav
Published: May 2021

Diffractive optical elements (DOEs) are used to shape the wavefront of incident light. This can be used to generate practically any pattern of interest, albeit with varying efficiency. A fundamental challenge associated with DOEs comes from the nanoscale-precision requirements for their fabrication. Here we demonstrate a method to controllably scale up the relevant feature dimensions of a device from tens-of-nanometers to tens-of-microns by immersing the DOEs in a near-index-matched solution. This makes it possible to utilize modern 3D-printing technologies for fabrication, thereby significantly simplifying the production of DOEs and decreasing costs by orders of magnitude, without hindering performance. We demonstrate the tunability of our design for varying experimental conditions, and the suitability of this approach to ultrasensitive applications by localizing the 3D positions of single molecules in cells using our microscale fabricated optical element to modify the point-spread-function (PSF) of a microscope.
Detecting and phasing minor single-nucleotide variants from long-read sequencing data
Authors: Feng Zhixing , Clemente Jose C. , Wong Brandon , Schadt Eric E.
Published: May 2021

Cellular genetic heterogeneity is common in many biological conditions including cancer, microbiome, and co-infection of multiple pathogens. Detecting and phasing minor variants play an instrumental role in deciphering cellular genetic heterogeneity, but they are still difficult tasks because of technological limitations. Recently, long-read sequencing technologies, including those by Pacific Biosciences and Oxford Nanopore, provide an opportunity to tackle these challenges. However, high error rates make it difficult to take full advantage of these technologies. To fill this gap, we introduce iGDA, an open-source tool that can accurately detect and phase minor single-nucleotide variants (SNVs), whose frequencies are as low as 0.2%, from raw long-read sequencing data. We also demonstrate that iGDA can accurately reconstruct haplotypes in closely related strains of the same species (divergence ≥0.011%) from long-read metagenomic data.
Predicting optimal deep brain stimulation parameters for Parkinson’s disease using functional MRI and machine learning
Authors: Boutet Alexandre , Madhavan Radhika , Elias Gavin J. B. , Joel Suresh E. , Gramer Robert , Ranjan Manish , Paramanandam Vijayashankar , Xu David , Germann Jurgen , Loh Aaron , Kalia Suneil K. , Hodaie Mojgan , Li Bryan , Prasad Sreeram , Coblentz Ailish , Munhoz Renato P. , Ashe Jeffrey , Kucharczyk Walter , Fasano Alfonso , Lozano Andres M.
Published: May 2021

Commonly used for Parkinson’s disease (PD), deep brain stimulation (DBS) produces marked clinical benefits when optimized. However, assessing the large number of possible stimulation settings (i.e., programming) requires numerous clinic visits. Here, we examine whether functional magnetic resonance imaging (fMRI) can be used to predict optimal stimulation settings for individual patients. We analyze 3 T fMRI data prospectively acquired as part of an observational trial in 67 PD patients using optimal and non-optimal stimulation settings. Clinically optimal stimulation produces a characteristic fMRI brain response pattern marked by preferential engagement of the motor circuit. Then, we build a machine learning model predicting optimal vs. non-optimal settings using the fMRI patterns of 39 PD patients with a priori clinically optimized DBS (88% accuracy). The model predicts optimal stimulation settings in unseen datasets: a priori clinically optimized and stimulation-naïve PD patients. We propose that fMRI brain responses to DBS stimulation in PD patients could represent an objective biomarker of clinical response. Upon further validation with additional studies, these findings may open the door to functional imaging-assisted DBS programming.
In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy
Authors: Dai Meiou , Yan Gang , Wang Ni , Daliah Girija , Edick Ashlin M. , Poulet Sophie , Boudreault Julien , Ali Suhad , Burgos Sergio A. , Lebrun Jean-Jacques
Published: May 2021

Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.
Subpolar North Atlantic western boundary density anomalies and the Meridional Overturning Circulation
Authors: Li F. , Lozier M. S. , Bacon S. , Bower A. S. , Cunningham S. A. , de Jong M. F. , deYoung B. , Fraser N. , Fried N. , Han G. , Holliday N. P. , Holte J. , Houpert L. , Inall M. E. , Johns W. E. , Jones S. , Johnson C. , Karstensen J. , Le Bras I. A. , Lherminier P. , Lin X. , Mercier H. , Oltmanns M. , Pacini A. , Petit T. , Pickart R. S. , Rayner D. , Straneo F. , Thierry V. , Visbeck M. , Yashayaev I. , Zhou C.
Published: May 2021

Changes in the Atlantic Meridional Overturning Circulation, which have the potential to drive societally-important climate impacts, have traditionally been linked to the strength of deep water formation in the subpolar North Atlantic. Yet there is neither clear observational evidence nor agreement among models about how changes in deep water formation influence overturning. Here, we use data from a trans-basin mooring array (OSNAP—Overturning in the Subpolar North Atlantic Program) to show that winter convection during 2014–2018 in the interior basin had minimal impact on density changes in the deep western boundary currents in the subpolar basins. Contrary to previous modeling studies, we find no discernable relationship between western boundary changes and subpolar overturning variability over the observational time scales. Our results require a reconsideration of the notion of deep western boundary changes representing overturning characteristics, with implications for constraining the source of overturning variability within and downstream of the subpolar region.
Addressing voltage decay in Li-rich cathodes by broadening the gap between metallic and anionic bands
Authors: Zhang Jicheng , Zhang Qinghua , Wong Deniz , Zhang Nian , Ren Guoxi , Gu Lin , Schulz Christian , He Lunhua , Yu Yang , Liu Xiangfeng
Published: May 2021

Oxygen release and irreversible cation migration are the main causes of voltage fade in Li-rich transition metal oxide cathode. But their correlation is not very clear and voltage decay is still a bottleneck. Herein, we modulate the oxygen anionic redox chemistry by constructing Li2ZrO3 slabs into Li2MnO3 domain in Li1.21Ni0.28Mn0.51O2, which induces the lattice strain, tunes the chemical environment for redox-active oxygen and enlarges the gap between metallic and anionic bands. This modulation expands the region in which lattice oxygen contributes capacity by oxidation to oxygen holes and relieves the charge transfer from anionic band to antibonding metal–oxygen band under a deep delithiation. This restrains cation reduction, metal–oxygen bond fracture, and the formation of localized O2 molecule, which fundamentally inhibits lattice oxygen escape and cation migration. The modulated cathode demonstrates a low voltage decay rate (0.45 millivolt per cycle) and a long cyclic stability.
Probing the Na metal solid electrolyte interphase via cryo-transmission electron microscopy
Authors: Han Bing , Zou Yucheng , Zhang Zhen , Yang Xuming , Shi Xiaobo , Meng Hong , Wang Hong , Xu Kang , Deng Yonghong , Gu Meng
Published: May 2021

Cryogenic transmission electron microscopy (cryo-TEM) is a valuable tool recently proposed to investigate battery electrodes. Despite being employed for Li-based battery materials, cryo-TEM measurements for Na-based electrochemical energy storage systems are not commonly reported. In particular, elucidating the chemical and morphological behavior of the Na-metal electrode in contact with a non-aqueous liquid electrolyte solution could provide useful insights that may lead to a better understanding of metal cells during operation. Here, using cryo-TEM, we investigate the effect of fluoroethylene carbonate (FEC) additive on the solid electrolyte interphase (SEI) structure of a Na-metal electrode. Without FEC, the NaPF6-containing carbonate-based electrolyte reacts with the metal electrode to produce an unstable SEI, rich in Na2CO3 and Na3PO4, which constantly consumes the sodium reservoir of the cell during cycling. When FEC is used, the Na-metal electrode forms a multilayer SEI structure comprising an outer NaF-rich amorphous phase and an inner Na3PO4 phase. This layered structure stabilizes the SEI and prevents further reactions between the electrolyte and the Na metal.
Construction 7-membered ring via Ni–Al bimetal-enabled C–H cyclization for synthesis of tricyclic imidazoles
Authors: Li Jiang-Fei , Xu Wei-Wei , Wang Rong-Hua , Li Yue , Yin Ge , Ye Mengchun
Published: May 2021

The construction of 7-membered ring via direct C7–H cyclization of benzoimidazoles with alkenes would provide a more atom- and step-economical route to tricyclic imidazoles and derivatives that widely exist in a broad range of bioactive molecules. However, transition metal-catalyzed C–H cyclization for medium-ring synthesis has been limited to reactive C–H bonds, instead, the activation of unreactive C–H bonds towards medium synthesis still remains an elusive challenge. Herein, we report a direct construction of 7-membered rings via Ni–Al co-catalyzed unreactive C7–H cyclization of benzoimidazoles with alkenes, providing a series of tricyclic imidazoles in 40–98% yield and with up to 95:5 er.
Anti-tumor effects of an ID antagonist with no observed acquired resistance
Authors: Wojnarowicz Paulina M. , Escolano Marta Garcia , Huang Yun-Han , Desai Bina , Chin Yvette , Shah Riddhi , Xu Sijia , Yadav Saurabh , Yaklichkin Sergey , Ouerfelli Ouathek , Soni Rajesh Kumar , Philip John , Montrose David C. , Healey John H. , Rajasekhar Vinagolu K. , Garland William A. , Ratiu Jeremy , Zhuang Yuan , Norton Larry , Rosen Neal , Hendrickson Ronald C. , Zhou Xi Kathy , Iavarone Antonio , Massague Joan , Dannenberg Andrew J. , Lasorella Anna , Benezra Robert
Published: May 2021

ID proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in cancer. ID proteins inhibit basic-HLH transcription factors often blocking differentiation and sustaining proliferation. A small-molecule, AGX51, targets ID proteins for degradation and impairs ocular neovascularization in mouse models. Here we show that AGX51 treatment of cancer cell lines impairs cell growth and viability that results from an increase in reactive oxygen species (ROS) production upon ID degradation. In mouse models, AGX51 treatment suppresses breast cancer colonization in the lung, regresses the growth of paclitaxel-resistant breast tumors when combined with paclitaxel and reduces tumor burden in sporadic colorectal neoplasia. Furthermore, in cells and mice, we fail to observe acquired resistance to AGX51 likely the result of the inability to mutate the binding pocket without loss of ID function and efficient degradation of the ID proteins. Thus, AGX51 is a first-in-class compound that antagonizes ID proteins, shows strong anti-tumor effects and may be further developed for the management of multiple cancers.
Large subglacial source of mercury from the southwestern margin of the Greenland Ice Sheet
Authors: Hawkings Jon R. , Linhoff Benjamin S. , Wadham Jemma L. , Stibal Marek , Lamborg Carl H. , Carling Gregory T. , Lamarche-Gagnon Guillaume , Kohler Tyler J. , Ward Rachael , Hendry Katharine R. , Falteisek Lukáš , Kellerman Anne M. , Cameron Karen A. , Hatton Jade E. , Tingey Sarah , Holt Amy D. , Vinšová Petra , Hofer Stefan , Bulínová Marie , Větrovský Tomáš , Meire Lorenz , Spencer Robert G. M.
Published: May 2021

The Greenland Ice Sheet is currently not accounted for in Arctic mercury budgets, despite large and increasing annual runoff to the ocean and the socio-economic concerns of high mercury levels in Arctic organisms. Here we present concentrations of mercury in meltwaters from three glacial catchments on the southwestern margin of the Greenland Ice Sheet and evaluate the export of mercury to downstream fjords based on samples collected during summer ablation seasons. We show that concentrations of dissolved mercury are among the highest recorded in natural waters and mercury yields from these glacial catchments (521–3,300 mmol km−2 year−1) are two orders of magnitude higher than from Arctic rivers (4–20 mmol km−2 year−1). Fluxes of dissolved mercury from the southwestern region of Greenland are estimated to be globally significant (15.4–212 kmol year−1), accounting for about 10% of the estimated global riverine flux, and include export of bioaccumulating methylmercury (0.31–1.97 kmol year−1). High dissolved mercury concentrations (~20 pM inorganic mercury and ~2 pM methylmercury) were found to persist across salinity gradients of fjords. Mean particulate mercury concentrations were among the highest recorded in the literature (~51,000 pM), and dissolved mercury concentrations in runoff exceed reported surface snow and ice values. These results suggest a geological source of mercury at the ice sheet bed. The high concentrations of mercury and its large export to the downstream fjords have important implications for Arctic ecosystems, highlighting an urgent need to better understand mercury dynamics in ice sheet runoff under global warming.
Patient characteristics predict patency of early-cannulation arteriovenous grafts
Authors: Kingsmore David B. , Stevenson Karen S. , Richarz S. , Isaak Andrej , Jackson Andrew , Kasthuri Ram , Thomson Peter C.
Published: May 2021

There is a new emphasis on tailoring appropriate vascular access for hemodialysis to patients and their life-plans, but there is little known about the optimal use of newer devices such as early-cannulation arteriovenous grafts (ecAVG), with studies utilising them in a wide variety of situations. The aim of this study was to determine if the outcome of ecAVG can be predicted by patient characteristics known pre-operatively. This retrospective analysis of 278 consecutive ecAVG with minimum one-year follow-up correlated functional patency with demographic data, renal history, renal replacement and vascular access history. On univariate analysis, aetiology of renal disease, indication for an ecAVG, the number of previous tunnelled central venous catheters (TCVC) prior to insertion of an ecAVG, peripheral vascular disease, and BMI were significant associates with functional patency. On multivariate analysis the number of previous TCVC, the presence of peripheral vascular disease and indication were independently associated with outcome after allowing for age, sex and BMI. When selecting for vascular access, understanding the clinical circumstances such as indication and previous vascular access can identify patients with differing outcomes. Importantly, strategies that result in TCVC exposure have an independent and cumulative association with decreasing long-term patency for subsequent ecAVG. As such, TCVC exposure is best avoided or minimised particularly when ecAVG can be considered.
Activation of IGF-1 pathway and suppression of atrophy related genes are involved in Epimedium extract (icariin) promoted C2C12 myotube hypertrophy
Authors: Lin Yi-An , Li Yan-Rong , Chang Yi-Ching , Hsu Mei-Chich , Chen Szu-Tah
Published: May 2021

The regenerative effect of Epimedium and its major bioactive flavonoid icariin (ICA) have been documented in traditional medicine, but their effect on sarcopenia has not been evaluated. The aim of this study was to investigate the effects of Epimedium extract (EE) on skeletal muscle as represented by differentiated C2C12 cells. Here we demonstrated that EE and ICA stimulated C2C12 myotube hypertrophy by activating several, including IGF-1 signal pathways. C2C12 myotube hypertrophy was demonstrated by enlarged myotube and increased myosin heavy chains (MyHCs). In similar to IGF-1, EE/ICA activated key components of the IGF-1 signal pathway, including IGF-1 receptor. Pre-treatment with IGF-1 signal pathway specific inhibitors such as picropodophyllin, LY294002, and rapamycin attenuated EE induced myotube hypertrophy and MyHC isoform overexpression. In a different way, EE induced MHyC-S overexpression can be blocked by AMPK, but not by mTOR inhibitor. On the level of transcription, EE suppressed myostatin and MRF4 expression, but did not suppress atrogenes MAFbx and MuRF1 like IGF-1 did. Differential regulation of MyHC isoform and atrogenes is probably due to inequivalent AKT and AMPK phosphorylation induced by EE and IGF-1. These findings suggest that EE/ICA stimulates pathways partially overlapping with IGF-1 signaling pathway to promote myotube hypertrophy.
A single neuron subset governs a single coactive neuron circuit in Hydra vulgaris, representing a possible ancestral feature of neural evolution
Authors: Noro Yukihiko , Shimizu Hiroshi , Mineta Katsuhiko , Gojobori Takashi
Published: May 2021

The last common ancestor of Bilateria and Cnidaria is believed to be one of the first animals to develop a nervous system over 500 million years ago. Many of the genes involved in the neural function of the advanced nervous system in Bilateria are well conserved in Cnidaria. Thus, the cnidarian Hydra vulgaris is a good model organism for the study of the putative primitive nervous system in its last common ancestor. The diffuse nervous system of Hydra consists of several peptidergic neuron subsets. However, the specific functions of these subsets remain unclear. Using calcium imaging, here we show that the neuron subsets that express neuropeptide, Hym-176, function as motor circuits to evoke longitudinal contraction. We found that all neurons in a subset defined by the Hym-176 gene (Hym-176A) or its paralogs (Hym-176B) expression are excited simultaneously, followed by longitudinal contraction. This indicates not only that these neuron subsets have a motor function but also that a single molecularly defined neuron subset forms a single coactive circuit. This is in contrast with the bilaterian nervous system, where a single molecularly defined neuron subset harbors multiple coactive circuits, showing a mixture of neurons firing with different timings. Furthermore, we found that the two motor circuits, one expressing Hym-176B in the body column and the other expressing Hym-176A in the foot, are coordinately regulated to exert region-specific contraction. Our results demonstrate that one neuron subset is likely to form a monofunctional circuit as a minimum functional unit to build a more complex behavior in Hydra. This simple feature (one subset, one circuit, one function) found in Hydra may represent the simple ancestral condition of neural evolution.