bluuebunny/crossref_metadata_2025 huggingface dataset:
Tutorial: unified 1D inversion of the acoustic reflection response
Authors: Slob Evert , Wapenaar Kees , Treitel Sven
Published: February 2020

Acoustic inversion in one‐dimension gives impedance as a function of travel time. Inverting the reflection response is a linear problem. Recursive methods, from top to bottom or vice versa, are known and use a fundamental wave field that is computed from the reflection response. An integral over the solution to the Marchenko equation, on the other hand, retrieves the impedance at any vertical travel time instant. It is a non‐recursive method, but requires the zero‐frequency value of the reflection response. These methods use the same fundamental wave field in different ways. Combining the two methods leads to a non‐recursive scheme that works with finite‐frequency bandwidth. This can be used for target‐oriented inversion. When a reflection response is available along a line over a horizontally layered medium, the thickness and wave velocity of any layer can be obtained together with the velocity of an adjacent layer and the density ratio of the two layers. Statistical analysis over 1000 noise realizations shows that the forward recursive method and the Marchenko‐type method perform well on computed noisy data.
Warming the phycosphere: Differential effect of temperature on the use of diatom‐derived carbon by two copiotrophic bacterial taxa
Authors: Arandia‐Gorostidi Nestor , Alonso‐Sáez Laura , Stryhanyuk Hryhoriy , Richnow Hans H. , Morán Xosé Anxelu G. , Musat Niculina
Published: February 2020

Heterotrophic bacteria associated with microphytoplankton, particularly those colonizing the phycosphere, are major players in the remineralization of algal‐derived carbon. Ocean warming might impact dissolved organic carbon (DOC) uptake by microphytoplankton‐associated bacteria with unknown biogeochemical implications. Here, by incubating natural seawater samples at three different temperatures, we analysed the effect of experimental warming on the abundance and C and N uptake activity of Rhodobacteraceae and Flavobacteria, two bacterial groups typically associated with microphytoplankton. Using a nano‐scale secondary ion mass spectrometry (nanoSIMS) single‐cell analysis, we quantified the temperature sensitivity of these two taxonomic groups to the uptake of algal‐derived DOC in the microphytoplankton associated fraction with 13C‐bicarbonate and 15N‐leucine as tracers. We found that cell‐specific 13C uptake was similar for both groups (~0.42 fg C h−1 μm−3), but Rhodobacteraceae were more active in 15N‐leucine uptake. Due to the higher abundance of Flavobacteria associated with microphytoplankton, this group incorporated fourfold more carbon than Rhodobacteraceae. Cell‐specific 13C uptake was influenced by temperature, but no significant differences were found for 15N‐leucine uptake. Our results show that the contribution of Flavobacteria and Rhodobacteraceae to C assimilation increased up to sixfold and twofold, respectively, with an increase of 3°C above ambient temperature, suggesting that warming may differently affect the contribution of distinct copiotrophic bacterial taxa to carbon cycling.
Protein expression in the obligate hydrocarbon‐degrading psychrophile Oleispira antarctica RB‐8 during alkane degradation and cold tolerance
Authors: Gregson Benjamin H. , Metodieva Gergana , Metodiev Metodi V. , Golyshin Peter N. , McKew Boyd A.
Published: February 2020

In cold marine environments, the obligate hydrocarbon‐degrading psychrophile Oleispira antarctica RB‐8, which utilizes aliphatic alkanes almost exclusively as substrates, dominates microbial communities following oil spills. In this study, LC–MS/MS shotgun proteomics was used to identify changes in the proteome induced during growth on n‐alkanes and in cold temperatures. Specifically, proteins with significantly higher relative abundance during growth on tetradecane (n‐C14) at 16°C and 4°C have been quantified. During growth on n‐C14, O. antarctica expressed a complete pathway for the terminal oxidation of n‐alkanes including two alkane monooxygenases, two alcohol dehydrogenases, two aldehyde dehydrogenases, a fatty‐acid‐CoA ligase, a fatty acid desaturase and associated oxidoreductases. Increased biosynthesis of these proteins ranged from 3‐ to 21‐fold compared with growth on a non‐hydrocarbon control. This study also highlights mechanisms O. antarctica may utilize to provide it with ecological competitiveness at low temperatures. This was evidenced by an increase in spectral counts for proteins involved in flagella structure/output to overcome higher viscosity, flagella rotation to accumulate cells and proline metabolism to counteract oxidative stress, during growth at 4°C compared with 16°C. Such species‐specific understanding of the physiology during hydrocarbon degradation can be important for parameterizing models that predict the fate of marine oil spills.
The Accuracy and Repeatability of Reconstructing Single Bullet Impacts Using the 2D Ellipse Method
Authors: Walters Miguel , Liscio Eugene
Published: February 2020

When a bullet punctures a surface, it leaves behind a bullet impact, which can be analyzed in order to determine the origin and trajectory path from which a bullet was discharged using many different scientific methods to reconstruct a shooting scene. The purpose of the research was to test the accuracy and repeatability of reconstructing the impact angle of single bullet impacts using the ellipse method. The research was conducted by firing various calibers of ammunition into drywall panels positioned at varying angles of incidence from 88° until ricochet occurred. This was done in order to determine which caliber type and angle of incidence are most accurate and precise for reconstructing a shooting scene. The study examined four caliber types fired into drywall panels, with 5 repeated shots for each of the 11 angles of incidence (n = 220). Furthermore, 31 participants partook in the study to estimate a bullet impact angle of incidence utilizing the ellipse method. The results show that the best performance (accuracy and repeatability) is seen with the measurements of the 0.45 caliber ammunition. When angle of incidences is low (<64°), the performance (accuracy and repeatability) was seen to be better in all caliber ammunitions. Overall, the data provided for single bullet impacts deposited in drywall show that the ellipse method is useful in providing measurements for most crime scene reconstruction purposes and has also demonstrated that results vary depending on the type of ammunition, firearm, and angle of incidence being examined.
Diversity of bacteria in different life stages and their impact on the development and reproduction of Zeugodacus tau (Diptera: Tephritidae)
Authors: Noman Md. Shibly , Shi Ge , Liu Li‐Jun , Li Zhi‐Hong
Published: February 2020

Fruit flies usually harbor diverse communities of bacteria in their digestive systems, which are known to play a significant role in their fitness. However, little information is available on Zeugodacus tau, a polyphagous pest worldwide. This study reports the first extensive analysis of bacterial communities in different life stages and their effect on the development and reproduction of laboratory‐reared Z. tau. Cultured bacteria were identified using the conventional method, and all bacteria were identified by high‐throughput technologies (16S ribosomal RNA gene sequencing of V3‒V4 region). A total of six bacterial phyla were identified in larvae, pupae, and male and female adult flies, which were distributed into 14 classes, 32 orders, 58 families and 96 genera. Proteobacteria was the most represented phylum in all the stages except larvae. Enterobacter, Klebsiella, Providencia, and Pseudomonas were identified by conventional and next‐generation sequencing analysis in both male and female adult flies, and Enterobacter was found to be the main genus. After being fed with antibiotics from the first instar larvae, bacterial diversity changed markedly in the adult stage. Untreated flies laid eggs and needed 20 days before oviposition while the treated flies showed ovary development inhibited and were not able to lay eggs, probably due to the alteration of the microbiota. These findings provide the cornerstone for unexplored research on bacterial function in Z. tau, which will help to develop an environmentally friendly management technique for this kind of harmful insect.
Impact of defelonizing drug possession on recidivism
Authors: Bird Mia , Nguyen Viet , Grattet Ryken
Published: February 2020

Research Summary

California's Proposition 47 (Prop 47), passed in November 2014, sought to scale back punishment for selected drug and property offenses, making them misdemeanors rather than felonies. Although others have examined the impacts of Proposition 47 on crime rates, here we examine the impacts on a range of recidivism outcomes specifically for individuals convicted for drug possession offenses. We focus on the defelonization of drug possession because nationally evidence suggests that public and policy maker sympathy for reducing incarceration use is greatest for nonviolent drug offenders. Thus, the greatest relevance of Proposition 47 to the nation lies in its strategy of defelonizing drug possession. We draw on an ongoing data collection effort on criminal justice populations in 12 California counties and link these data to rearrest and reconviction data from county and state‐level sources. We find people who received drug possession convictions after Prop 47 had lower overall rearrest and reconviction rates than people with comparable convictions and criminal histories released prior to the proposition. Overall reductions in recidivism rates for Prop 47 drug offenders were driven by reductions in rearrest and reconviction for drug possession offenses. These findings are robust to a variety of specifications and sensitivity analyses. When we complicate the narrative of declines in nonviolent recidivism, however, we find evidence of a 2.8‐percentage‐point increase in rearrest for crimes against persons, mainly assaults and domestic violence. Reconviction rates for crimes against persons for drug possession offenders also increased by 1.1 percentage points.

Policy Implications

These findings add to the growing body of evidence that a targeted reform like Prop 47 does not result in increases in most measures of reoffending for people convicted of drug possession. Although we cannot rule out that the declines we observe in rearrest and reconviction are the result of behavioral change among offenders, it seems likely that those declines are partly, perhaps mostly, the result of changing decision‐making among law enforcement and prosecutors. Converting drug possession to be chargeable only as a misdemeanor has significantly reduced the likelihood individuals convicted of drug possession will return to jail or prison once they have been released and therefore stemmed some of the flow of people with such offenses through the system. Evidence from California, however, shows that there can be small increases in crimes against persons, which provides a cautionary note and points to the need to consider interventions that do not involve criminal justice responses in response to the negative aspects of drug use. Our conclusion discusses considerations in applying our findings to other states that have defelonized drug possession.
Examining the state repression‐terrorism nexus: Dynamic relationships among repressive counterterrorism actions, terrorist targets, and deadly terrorist violence in Israel
Authors: Hsu Henda Y. , McDowall David
Published: February 2020

Research Summary

This study assesses the impact of state repressive counterterrorism actions on terrorists’ targeting and lethality of the terrorism landscape in Israel. Using systematic data on government responses to terrorism and an empirical model that addresses reciprocal relationships, we analyze dynamical interactions between types of government repression with attacks against civilian or government targets, and deadly terrorist violence. Contrary to public policy pronouncements of forcefully fighting terrorism to eradicate terrorist threats, our results suggest that repressive counterterrorism actions by the state increase terror and deadly violence. Importantly, the results indicate that these unintended escalatory or backlash effects are dependent on the scope of government repression, the type of terrorist targets, and the lethality of terrorism.

Policy Implications

Our findings provide insight into particular behaviors and exchanges within the state repression–terrorism nexus that evoke and prolong terrorist violence. Centered on key aspects of terrorist activities involving target choice and deadly violence, our ecological study contributes to the development of a systematic understanding of specific impacts of government policies on terrorism. In all, constructing an empirically rigorous evidence base for terrorism prevention policies and practices is essential for ensuring the protection of human lives and public resources from terrorism.
Widespread microbial mercury methylation genes in the global ocean
Authors: Villar Emilie , Cabrol Léa , Heimbürger‐Boavida Lars‐Eric
Published: February 2020

Methylmercury is a neurotoxin that bioaccumulates from seawater to high concentrations in marine fish, putting human and ecosystem health at risk. High methylmercury levels have been found in the oxic subsurface waters of all oceans, but only anaerobic microorganisms have been shown to efficiently produce methylmercury in anoxic environments. The microaerophilic nitrite‐oxidizing bacteria Nitrospina have previously been suggested as possible mercury methylating bacteria in Antarctic sea ice. However, the microorganisms responsible for processing inorganic mercury into methylmercury in oxic seawater remain unknown. Here, we show metagenomic and metatranscriptomic evidence that the genetic potential for microbial methylmercury production is widespread in oxic seawater. We find high abundance and expression of the key mercury methylating genes hgcAB across all ocean basins, corresponding to the taxonomic relatives of known mercury methylating bacteria from Deltaproteobacteria, Firmicutes and Chloroflexi. Our results identify Nitrospina as the predominant and widespread microorganism carrying and actively expressing hgcAB. The highest hgcAB abundance and expression occurs in the oxic subsurface waters of the global ocean where the highest MeHg concentrations are typically observed.
IL‐1β prevents ILC2 expansion, type 2 cytokine secretion, and mucus metaplasia in response to early‐life rhinovirus infection in mice
Authors: Han Mingyuan , Ishikawa Tomoko , Bermick Jennifer R. , Rajput Charu , Lei Jing , Goldsmith Adam M. , Jarman Caitlin R. , Lee Julie , Bentley J. Kelley , Hershenson Marc B.
Published: February 2020

Background

Early‐life wheezing‐associated respiratory infection with human rhinovirus (RV) is associated with asthma development. RV infection of 6‐day‐old immature mice causes mucous metaplasia and airway hyperresponsiveness which is associated with the expansion of IL‐13‐producing type 2 innate lymphoid cells (ILC2s) and dependent on IL‐25 and IL‐33. We examined regulation of this asthma‐like phenotype by IL‐1β.

Methods

Six‐day‐old wild‐type or NRLP3−/− mice were inoculated with sham or RV‐A1B. Selected mice were treated with IL‐1 receptor antagonist (IL‐1RA), anti‐IL‐1β, or recombinant IL‐1β.

Results

Rhinovirus infection induced Il25, Il33, Il4, Il5, Il13, muc5ac, and gob5 mRNA expression, ILC2 expansion, mucus metaplasia, and airway hyperresponsiveness. RV also induced lung mRNA and protein expression of pro‐IL‐1β and NLRP3 as well as cleavage of caspase‐1 and pro‐IL‐1β, indicating inflammasome priming and activation. Lung macrophages were a major source of IL‐1β. Inhibition of IL‐1β signaling with IL‐1RA, anti‐IL‐1β, or NLRP3 KO increased RV‐induced type 2 cytokine immune responses, ILC2 number, and mucus metaplasia, while decreasing IL‐17 mRNA expression. Treatment with IL‐1β had the opposite effect, decreasing IL‐25, IL‐33, and mucous metaplasia while increasing IL‐17 expression. IL‐1β and IL‐17 each suppressed Il25, Il33, and muc5ac mRNA expression in cultured airway epithelial cells. Finally, RV‐infected 6‐day‐old mice showed reduced IL‐1β mRNA and protein expression compared to mature mice.

Conclusion

Macrophage IL‐1β limits type 2 inflammation and mucous metaplasia following RV infection by suppressing epithelial cell innate cytokine expression. Reduced IL‐1β production in immature animals provides a mechanism permitting asthma development after early‐life viral infection.
Therapeutic use of pulsed electromagnetic field therapy reduces prostate volume and lower urinary tract symptoms in benign prostatic hyperplasia
Authors: Tenuta Marta , Tarsitano Maria G. , Mazzotta Paola , Lucchini Livia , Sesti Franz , Fattorini Giorgio , Pozza Carlotta , Olivieri Valerio , Naro Fabio , Gianfrilli Daniele , Lenzi Andrea , Isidori Andrea M. , Pofi Riccardo
Published: February 2020

Background

Benign prostatic hyperplasia (BPH) etiology remains poorly understood, but chronic low‐grade inflammation plays a role. Pulsed electromagnetic field therapy (PEMF) (1‐50 Hz) is effective in reducing tissue inflammation.

Objectives

We designed a pilot study to evaluate the effects of PEMF on prostate volume (PV) in BPH.

Materials and Methods

This is a prospective interventional trial on 27 naive patients with BPH and lower urinary tract symptoms (LUTS). At baseline (V0), all patients had blood tests, transrectal ultrasound, and questionnaires (IPSS, IIEF‐15) and received a perineal PEMF device (Magcell®Microcirc, Physiomed Elektromedizin). PEMF was delivered on perineal area 5 minutes twice daily for 28 days, then (V1) all baseline evaluations were repeated. Afterward, nine patients continued therapy for 3 more months (PT group) and 15 discontinued (FU group). A 4‐month evaluation (V2) was performed in both groups.

Results

A reduction was observed both at V1 and at V2 in PV: PVV0 44.5 mL (38.0;61.6) vs PVV1 42.1 mL (33.7;61.5, P = .039) vs PVV2 41.7mL (32.7;62.8, P = .045). IPSS was reduced both at V1 and at V2: IPSSV0 11 (5.7;23.2) vs IPSSV1 10 (6;16, P = .045) vs IPSSV2 9 (6;14, P = .015). Baseline IPSS was related to IPSS reduction both at V1 (rs = 0.313;P = .003) and at V2 (rs = 0.664;P < .001). PV reduction in patients without metabolic syndrome (ΔPVV1nMetS −4.7 mL, 95%CI −7.3;‐2.0) was greater than in affected patients (ΔPVV1MetS 1.7 mL, 95%CI −2.69;6.1)(P = .017, Relative RiskMetS = 6). No changes were found in gonadal hormones or sexual function.

Discussion

PEMF was able to reduce PV after 28 days of therapy. Symptoms improved in a short time, with high compliance and no effects on hormonal and sexual function or any side effects. Patients with moderate‐severe LUTS and without MetS seem to benefit more from this treatment.

Conclusion

PEMF reduces PV and improves LUTS in a relative short time, in BPH patients. These benefits seem greater in those patients with moderate‐severe LUTS but without MetS.
The Social Life of Robots: The Politics of Algorithms, Governance, and Sovereignty
Authors: Del Casino Vincent J. , House‐Peters Lily , Crampton Jeremy W. , Gerhardt Hannes
Published: February 2020

This symposium aims to broaden the way scholars theorise and empirically treat the increasingly complex relationships between robots and social life, especially in the context of our historically anthropocentric human geographies. The authors of this symposium engage a range of diverse epistemological, ontological, and methodological commitments, but all in some way address the power dynamics and shifting political economies involved in human–robotic interactions as well as possibilities for resisting and overcoming particular forms of domination and oppression. At the same time, the papers present new avenues for conceptualising the rise of robots and robotics and the everyday socio‐spatial relations of contemporary algorithmic life. In a rapidly evolving present and future, where life is increasingly managed in relation to algorithmic imaginaries and automated fantasies, these papers demonstrate the potential for geographers to make significant interventions and contributions to investigate the limits, contradictions, and messy contingencies of socio‐technical assemblages, to trace the shifting spatialities and temporalities of the geographies of algorithmic governance, and to envision radical democratic, post‐capitalist, emancipatory alternatives. These futures are unlikely to be “robot free”, so the question remains how will we build a future set of geographies that acknowledges this reality while also claiming space for the diverse and rich expansion of all forms of life, both human and non‐human?
Type‐I interferon regulates matrix metalloproteinases clearance of the bovine endometrial spheroid
Authors: Rahman Al‐Nur Md. Iftekhar , Yamashita Seiya , Islam Md. Rashedul , Fujihara Taisuke , Yamaguchi Hayato , Kawahara Manabu , Takahashi Masashi , Takahashi Hideyuki , Gotoh Takafumi , Yamauchi Nobuhiko
Published: February 2020

This study investigated the effect of type‐I interferon (IFN) on the expression of matrix metalloproteinases (MMPs) of the bovine endometrial stromal cells (BES) and epithelial cells (BEE). The cells were separated and purified from the caruncles and cultured in DMEM/F‐12 containing 10% fetal bovine serum. Spheroids were generated by using ascorbate. Zymograms of the supernatant showed that BEE predominantly expressed MMP‐9, whereas MMP‐2 was expressed in BES and homo‐spheroids. While MMPs expression was not detected in hetero‐spheroids. Real‐time quantitative PCR revealed that type‐I IFN and P4 suppressed the gene expression of MMP‐2 and MMP‐9 in hetero‐spheroids, respectively. On the other hand, gelatin zymography analysis of the supernatant showed that type‐I IFN strongly promote the clearance of MMPs. While zymograms of the MMPs stocked in the hetero‐spheroids were significantly reduced by type‐I IFN. Phenylmethanesulfonyl fluoride and leupeptin (both are serine proteinase inhibitors) significantly repressed the clearance of MMP‐2 and MMP‐9 induced by type‐I IFN. Moreover, collagen fibers in hetero‐spheroids significantly decreased after the treatment with type‐I IFN. In conclusion, it was suggested that type‐I IFN participate in the tissue remodeling by regulation the clearance of MMPs.
CYP2D6 polymorphism and its impact on the clinical response to metoprolol: A systematic review and meta‐analysis
Authors: Meloche Maxime , Khazaka Michael , Kassem Imad , Barhdadi Amina , Dubé Marie‐Pierre , de Denus Simon
Published: February 2020

Aims

CYP2D6 genetic polymorphisms are associated with metoprolol pharmacokinetics. Whether the clinical response to metoprolol is also affected remains uncertain.

Methods

We conducted a systematic review on the effects of CYP2D6 polymorphism on the clinical response to metoprolol. Searches were conducted using MEDLINE. Meta‐analyses were performed on the impact of CYP2D6‐inferred phenotypes on heart rate (HR) reduction, diastolic (DBP) and systolic (SBP) blood pressure reduction, average daily doses, all‐type adverse events and bradycardia.

Results

Our qualitative assessment indicated inconsistent results in individual studies and endpoints, but CYP2D6 poor metabolizers (PM) generally presented a greater reduction in HR. The meta‐analysis of 15 studies, including a total of 1146 individuals, found a reduction in HR of 3 beats/min (P = .017), and of SBP and DBP by 3 mmHg (P = .0048) for PM compared to non‐PM individuals using similar metoprolol doses. Bradycardia appeared more frequent by 4‐fold for PM, although significant heterogeneity was observed regarding bradycardia, which limits the scope of this finding.

Conclusion

Patients without any CYP2D6 metabolic capacities appear to have increased reduction in DBP, HR and SBP during metoprolol treatment and may be at a higher risk of bradycardia compared to patients with active CYP2D6 phenotypes. Further prospective data are required to determine whether CYP2D6 is associated with clinical events in patients treated with metoprolol, as well as to demonstrate the clinical utility of an individualized approach of prescribing metoprolol using CYP2D6‐inferred phenotypes.
The ethics of risk displacement in research and public policy
Authors: Vong Gerard , Levinson Meira
Published: February 2020

We identify three distinct ethical problems that can arise with risk displacement. Risk displacement is the shifting of extant risk from one or more individuals to other individual(s) such that the reduction of risk to the first group is causally implicated in increasing risk to the second group. These problems are: concentration of risk in inequitable ways; transfer of risk to already vulnerable or disadvantaged populations; and exercise of undue influence over potential research participants. The first two arise in both public policy and research initiatives, whereas the third is a special concern that only applies to research initiatives. We argue that when one or more of these is of high magnitude, then the study or policy intervention may be ethically wrong. Finally, we conclude that although some risk displacement is ethically permissible, researchers and policymakers still have ethical reasons to reduce the magnitude of these problems.
CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance
Authors: Wilhelmson Anna S. , Porse Bo T.
Published: February 2020

Recent advances in sequencing technologies have allowed for the identification of recurrent mutations in acute myeloid leukaemia (AML). The transcription factor CCAAT enhancer binding protein alpha (CEBPA) is frequently mutated in AML, and biallelic CEBPA‐mutant AML was recognised as a separate disease entity in the recent World Health Organization classification. However, CEBPA mutations are co‐occurring with other aberrations in AML, and together these lesions form the clonal hierarchy that comprises the leukaemia in the patient. Here, we aim to review the current understanding of co‐occurring mutations in CEBPA‐mutated AML and their implications for disease biology and clinical outcome. We will put emphasis on patterns of cooperation, how these lesions cooperate with CEBPA mutations and the underlying potential molecular mechanisms. Finally, we will relate this to patient outcome and future options for personalised medicine.
Detection of measurable residual disease may better predict outcomes than mutations based on next‐generation sequencing in acute myeloid leukaemia with biallelic mutations of CEBPA
Authors: Wang Jing , Lu RunQing , Wu Ying , Jia JinSong , Gong Lizhong , Liu XiaoHong , Lu ShengYe , Wang Yu , Yan ChenHua , Liu KaiYan , Zhang XiaoHui , Xu LanPing , Jiang Qian , Zhao XiaoSu , Shi HongXia , Lai YueYun , Huang XiaoJun , Ruan GuoRui , Jiang Hao
Published: February 2020

Acute myeloid leukaemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30–50% relapse rate. This study established the value of mutations based on next‐generation sequencing (NGS) and multiparameter flow cytometric measurable residual disease (MFC‐MRD) detection and compared the outcomes. From 2014 to 2018, 124 newly diagnosed bi CEBPA AML patients were treated. The median age was 37·5 (16–69) years. The 3‐year cumulative incidence of relapse (CIR), relapse‐free survival (RFS) and overall survival (OS) were 33·0%, 64·7% and 84·3%, respectively. Patients without additional mutations and with GATA2 mutations were defined as ‘NGS low risk’, which was the only favourable independent factor for CIR and RFS of pretreatment parameters. Patients with sustained positive MRD after two consolidation cycles and MRD negative losses at any time were defined as ‘MRD high risk’, which was the only poor independent factor for CIR, RFS and OS, including pretreatment and post‐treatment parameters. In CR2 and non‐remission patients who underwent allo‐HSCT, superior OS was achieved. We conclude that NGS low risk was a favourable factor in the analysis of pretreatment parameters. MRD risk stratification was an independent prognostic factor in pretreatment and post‐treatment parameters. Relapsed patients still have a favourable outcome followed by allo‐HSCT.
OATP1A/1B, CYP3A, ABCB1, and ABCG2 limit oral availability of the NTRK inhibitor larotrectinib, while ABCB1 and ABCG2 also restrict its brain accumulation
Authors: Wang Yaogeng , Sparidans Rolf W. , Li Wenlong , Lebre Maria C. , Beijnen Jos H. , Schinkel Alfred H.
Published: February 2020

Background and Purpose

Larotrectinib is a FDA‐approved oral small‐molecule inhibitor for treatment of neurotrophic tropomyosin receptor kinase fusion‐positive cancer. We here investigated the functions of the multidrug efflux transporters ABCB1 and ABCG2, the SLCO1A/1B (OATP1A/1B) uptake transporters, and the multispecific drug‐metabolizing enzyme CYP3A in larotrectinib pharmacokinetic behaviour.

Experimental Approach

In vitro, transepithelial drug transport and uptake assays were performed.

In vivo, larotrectinib (10 mg·kg−1) was administered orally to relevant genetically modified mouse models. Cell medium, plasma samples, and organ homogenates were measured by a sensitive and specific LC–MS/MS larotrectinib assay.

Key Results

In vitro, larotrectinib was avidly transported by human (h) ABCB1 and mouse (m) Abcg2 efficiently by hABCG2 and modestly by hOATP1A2. In vivo, both mAbcb1a/1b and mAbcg2 markedly limited larotrectinib oral availability and brain and testis accumulation (by 2.1‐fold, 10.4‐fold, and 2.7‐fold, respectively), with mAbcb1a/1b playing a more prominent role. mOatp1a/1b also restricted larotrectinib oral availability (by 3.8‐fold) and overall tissue exposure, apparently by mediating substantial uptake into the liver, thus likely facilitating hepatobiliary excretion. Additionally, larotrectinib is an excellent substrate of CYP3A, which restricts the oral availability of larotrectinib and hence its tissue exposure.

Conclusions and Implications

ABCG2 and especially ABCB1 limit the oral availability and brain and testis penetration of larotrectinib, while OATP1A/1B transporters restrict its systemic exposure by mediating hepatic uptake, thus allowing hepatobiliary excretion. CYP3A‐mediated metabolism can strongly limit larotrectinib oral availability and hence its tissue concentrations. These insights may be useful in the further clinical development of larotrectinib.
The role of family centres in reducing social isolation in deprived communities
Authors: Mercer Fiona , Darbyshire Chris , Finlayson Janet , Kettle Martin , Dickson Adele
Published: February 2020

Social exclusion and isolation are worldwide social and health concerns with negative effects becoming exacerbated in deprived communities. There is limited understanding related to the role of community‐based centres in reducing social exclusion and isolation, so the aim of this research was to explore the role one family centre had in improving social inclusion in a deprived community in Glasgow, Scotland. Interpretative Phenomenological Analysis was utilized to analyse interviews from 10 parents to explore their lived experiences of creating and developing social networks through family centre attendance. Findings indicate that attending the family centre positively impacted on social inclusion and social support for all parents interviewed. Relationships created in the centre were proposed as being meaningful, non‐judgemental and produced social capital—rooted in reciprocity and trust. Findings can inform services that aim to reduce social isolation in deprived communities.
upd(20)mat is a rare cause of the Silver‐Russell‐syndrome‐like phenotype: Two unrelated cases and screening of large cohorts
Authors: Hjortshøj Tina D. , Sørensen Anna R. , Yusibova Melodi , Hansen Bo M. , Dunø Morten , Balslev‐Harder Marie , Grønskov Karen , van Hagen Johanna M. , Polstra Abeltje M. , Eggermann Thomas , Finken Martijn J.J. , Tümer Zeynep
Published: February 2020

Silver‐Russell syndrome (SRS) is an imprinting disorder characterized by prenatal and postnatal growth retardation, relative macrocephaly, feeding difficulties and body asymmetry. Recently, upd(20)mat has been identified in few patients with SRS‐like features, suggestive of a new imprinting disorder characterized by prenatal and postnatal growth failure. Here, we describe two male patients with upd(20) and feeding difficulties, prenatal and postnatal growth retardation and normal cognitive development. During pregnancy, confined placental mosaicism for trisomy 20 was detected in one of the patients but was not investigated further until identification of upd(20)mat in the neonatal period. To evaluate whether upd(20)mat should be part of the first trier genetic diagnostic in patients with growth retardation, we screened a large cohort of patients (n = 673) referred to our laboratories for SRS‐testing without detecting any upd(20). Our results, along with the existing evidence, indicate that upd(20)mat is a very rare cause of growth retardation, but should be followed up when confined placental mosaicism for trisomy 20 mosaicism is observed during pregnancy.
Teleological Essentialism: Generalized
Authors: Rose David , Nichols Shaun
Published: February 2020

Natural/social kind essentialism is the view that natural kind categories, both living and non‐living natural kinds, as well as social kinds (e.g., race, gender), are essentialized. On this view, artifactual kinds are not essentialized. Our view—teleological essentialism—is that a broad range of categories are essentialized in terms of teleology, including artifacts. Utilizing the same kinds of experiments typically used to provide evidence of essentialist thinking—involving superficial change (study 1), transformation of insides (study 2), and inferences about offspring (study 3)—we find support for the view that a broad range of categories—living natural kinds, non‐living natural kinds, and artifactual kinds—are essentialized in terms of teleology. Study 4 tests a unique prediction of teleological essentialism and also provides evidence that people make inferences about purposes which in turn guide categorization judgments.
Protection status and proximity to public‐private boundaries influence land use intensification near U.S. parks and protected areas
Authors: Vukomanovic Jelena , Singh Kunwar K. , Vogler John B. , Meentemeyer Ross K.
Published: February 2020

Public parks and protected areas are highly valued resources for recreation, education, and conservation of species and ecosystems. Increased demand for exurban lifestyles near protected areas may threaten these services, but to date research has been limited to case studies or considered only the most protected areas. We quantified changes (1990–2010) in the density of residential housing and impervious surface within 1, 10, 25, and 50 km of 6,644 U.S. protected areas, from highly protected national parks and wilderness areas to less protected game reserves and recreation areas. In almost all cases, housing density and impervious surface near protected areas were significantly higher than what would be expected by chance. Lands near protected areas with the highest level of protection (GAP I) experienced the greatest overall increase in housing and impervious area over time, but––contrary to earlier projections––little change occurred within 1 km of private‐public boundaries. An opposite pattern occurred near the least protected areas (GAP IV)––lands immediately adjacent to these parks experienced the largest rates of change, but this growth decreased further from their boundaries. Most of the changes near GAP IV areas occurred in the Eastern Temperate Forest ecoregion, though the greatest overall rates of land change occurred in the Southwest. Our findings suggest that previous studies may overestimate the extent to which housing growth broadly threatens conservation of U.S. protected areas. For the first time, we demonstrate that land change near protected areas varies by protection status, proximity to public‐private boundaries, and ecoregion. To make these data more accessible to practitioners, we have created an interactive, online mapping platform that allows anyone to explore location‐specific trends in land change near parks and protected areas.
Transcranial magnetic stimulation as a biomarker of treatment response in children with epilepsy
Authors: Balestrini Simona , Sander Josemir W
Published: February 2020

This commentary is on the original article by Andreasson et al. on pages 793–798 of this issue.
A Doppler ghost in the pulmonary artery
Authors: Cagli Kumral , Ozbulbul Nilgun Isıksalan , Ozeke Ozcan , Calapkulu Muhammed Yunus , Golbasi Zehra
Published: February 2020

Long‐standing left‐to‐right shunting across a patent ductus arteriosus (PDA) can result in Eisenmenger syndrome. In this report, we present echocardiographic findings of a 27‐year‐old female patient with pulmonary hypertension. In diagnostic work‐up especially Doppler findings of the pulmonary artery suggested the presence of a reversed PDA as a cause of pulmonary hypertension. The diagnosis was confirmed by contrast study and computed tomography.
It is more than Interference: Examining the neurohemodynamic correlates of the flanker task with functional near‐infrared spectroscopy
Authors: Geissler (Geißler) Christoph F. , Hofmann Markus J. , Frings Christian
Published: February 2020

Previous functional near‐infrared spectroscopy studies using the Eriksen flanker task, in contrast to functional magnetic resonance imaging studies, revealed the quite puzzling finding of an inverted conflict effect, that is, greater middle and superior frontal activation in response compatible than in response incompatible trials. However, since neither prior functional near‐infrared spectroscopy studies nor most previous functional magnetic resonance imaging studies separated between an identical and a compatible condition, it is hard to pinpoint whether this discrepancy occurs on the level of stimulus processing or response generation. By assigning two letters to both left (D, F) and right (J, K) hand reactions, we were able to separate identical (e.g., JJJ) and compatible (e.g., JKJ) conditions that solely differ in their stimulus congruency. Replicating prior functional magnetic resonance imaging findings, we found the standard conflict effect at the transition of superior and middle frontal gyrus, when comparing the activation in compatible trials to that in incompatible trials. Both changes in oxygenated and deoxygenated hemoglobin thus pointed to more effortful processing in incompatible trials. Interestingly, however, identical trials showed the highest activation in this region, according to both changes in oxygenated and deoxygenated blood. A finding that mirrors and extends prior functional near‐infrared spectroscopy findings, which only regarded oxygenated blood. We argue that this pattern of results does not reflect the standard conflict effect. We rather assume that other processes like perceptual familiarity or strategic readjustment might be at play.
The industries of the future in Mexico: Local and non‐local effects in the localization of “knowledge‐intensive services”
Authors: Santiago Luis Enrique
Published: February 2020

The current characteristics in the global economy have defined “knowledge‐intensive services” (KIS) as part of the so‐called “industries of the future” due to the attributes of their employment and central function in the development processes in science, technology, art, and culture. This study outlines as a central hypothesis that the localization of KIS depends on different factors according to the type of knowledge being developed (analytical, synthetic, and symbolic). The main objective in this work is to explore the spatial economic factors associated with the localization and changes (positive and negative) when using KIS in the “national urban system” in México between 2004 and 2014. To do so, the services sector is defined according to the “intensity” and the “types” of knowledge that they develop. An analysis of spatial econometrics is carried out that distinguishes between the geographic (local) effect and the spatial (non‐local) effect of the independent variables using data and microdata from the period 2004 to 2014. The results partly correspond with the central hypothesis of the study and offer possibilities of public policies to take advantage of and to promote the benefits of KIS, especially regarding cities in developing countries looking to become part of the 21st century economy.
Accuracy of the Enhanced Liver Fibrosis test, and combination of the Enhanced Liver Fibrosis and non‐invasive tests for the diagnosis of advanced liver fibrosis in patients with non‐alcoholic fatty liver disease
Authors: Inadomi Chika , Takahashi Hirokazu , Ogawa Yuji , Oeda Satoshi , Imajo Kento , Kubotsu Yoshihito , Tanaka Kenichi , Kessoku Takaomi , Okada Michiaki , Isoda Hiroshi , Akiyama Takumi , Fukushima Hideaki , Yoneda Masato , Anzai Keizo , Aishima Shinichi , Nakajima Atsushi , Eguchi Yuichiro
Published: February 2020

Aim

The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non‐alcoholic fatty liver disease.

Methods

ELF cut‐off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy‐confirmed non‐alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224).

Results

The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut‐off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut‐off 10.83) and LSM (cut‐off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis‐4 index (cut‐off 2.67) and ELF (cut‐off 9.34) increased the sensitivity to 95.9%.

Conclusions

ELF can identify advanced liver fibrosis in non‐alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non‐invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.
Biocompatible green tea extract‐stabilised zinc nanoparticles encapsulated by poly(butyl‐2‐cyanoacrylate) with control release profile and antioxidative capacity
Authors: Yao Jing‐Jing , Zhang Peng , Fu Zhou‐Ping , Xie Zhong‐Wen , Bao Guan‐Hu
Published: February 2020

Green tea extract‐stabilised Zn nanoparticles (GT‐Zn NPs) encapsulated by poly(butyl‐2‐cyanoacrylate) (PBCA@GT‐Zn NPs) were developed for control release of Zn. The crucial parameters, concentrations of GT‐Zn NPs and the monomer n‐butyl‐2‐cyanoacrylate (BCA), which affected the size, polydispersity indexes (PDI) and encapsulation efficiency (EE %), were evaluated to achieve the smaller size, higher EE (%) and stably and uniformly dispersed NPs. The optimised PBCA@GT‐Zn NPs with <100 nm diameter (46.38 ± 3.46 by SEM, 86.91 ± 3.66 by DLS), PDI (0.159 ± 0.042), zeta potential (−20.56 ± 2.53 mV) and EE (89.31 ± 1.09 %) were obtained. In vitro release of Zn ions was conducted at pH 7.4, showing that Zn from the self‐made tablets and lyophilised PBCA@GT‐Zn NPs is released significantly slower than that of GT‐Zn NPs. Additionally, the PBCA@GT‐Zn NP tablets are pH‐responsive, non‐toxic and antioxidative, suggesting that they could be used as safe food material or drug carriers, contributing to relieve Zn deficiency.
Over‐expression of RNA interference (RNAi) core machinery improves susceptibility to RNAi in silkworm larvae
Authors: You L. , Zhang F. , Huang S. , Merchant A. , Zhou X. , Li Z.
Published: February 2020

RNA interference (RNAi), one of the strategies that organisms use to defend against invading viruses, is an important tool for functional genomic analysis. In insects, the efficacy of RNAi varies amongst taxa. Lepidopteran insects are, in large part, recalcitrant to RNAi. The overall goal of this study is to overcome such insensitivity in lepidopterans to RNAi. We hypothesize that over‐expression of core RNAi machinery enzymes can improve RNAi efficacy in traditionally recalcitrant species. A transgenic Bombyx mori strain, Baculovirus Immediate‐Early Gene, ie1, promoter driven expression of silkworm Dicer2 coding sequence (IE1‐BmDicer2), which over‐expresses BmDicer2, was generated by piggyBac transposon‐mediated transgenesis. Two indexes, the ratio of animals that showed a silencing phenotype and the duration of silencing, were used to evaluate silencing efficiency. Significant knockdown of target gene expression was observed at 48 h postinjection at both the transcriptional and translational levels. Furthermore, we coexpressed B. mori Argonaute 2 BmAgo2）and BmDicer 2 and found that 22% of the animals (n = 18) showed an obvious silencing effect even at 72 h, suggesting that coexpression of these two RNAi core machinery enzymes further increased the susceptibility of B. mori to injected double‐stranded RNAs. This study offers a new strategy for functional genomics research in RNAi‐refractory insect taxa in general and for lepidopterans in particular.
Group A streptococcal bacteraemia at a tertiary hospital in Melbourne: concern of an under‐reported risk group in Australia
Authors: Attwood Lucy O. , Spelman Denis
Published: February 2020

Background

Invasive group A streptococcal (iGAS) infections are increasing worldwide with at‐risk groups being children, pregnant women and the elderly. In 2017, there was a rise in iGAS cases in Victoria, prompting a Chief Health Officer advisory.

Aims

To describe the characteristics of patients with GAS bacteraemia admitted to a tertiary hospital. To compare at‐risk groups in our population with those identified in the Victorian Government health alert.

Methods

Retrospective review of patients with GAS bacteraemia admitted between June 2014 and December 2017 at a tertiary hospital in Melbourne, Victoria.

Results

Forty‐three cases of GAS bacteraemia occurred. Average age was 52 years (range 15–88 years) with 63% male. Average length of stay was 14 days (range 0–72 days) and all‐cause mortality occurred in two (5%) cases.

Twelve (28%) patients presented with shock, 11 (26%) required intensive care unit admission and 13 (30%) surgical intervention. A history of intravenous drug use was documented in 18 (42%) cases and was commonly complicated by bone or joint involvement or thrombosis. Typing of GAS samples identified 22 different emm‐types.

Conclusion

GAS bacteraemia resulted in significant morbidity and prolonged hospitalisation. In contrast to the at‐risk groups identified in the Victorian Government health advisory, the commonest risk group in this series were people who inject drugs and most commonly middle‐aged men. Invasive GAS should be considered if a person who injects drugs presents with acute severe sepsis.